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Rutgers University
1.
Zucco, Avery, 1990-.
The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex.
Degree: PhD, Neuroscience, 2018, Rutgers University
URL: https://rucore.libraries.rutgers.edu/rutgers-lib/59301/ 
► Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by the mutation of either the TSC1 or TSC2 genes and characterized by the presence…
(more)
▼ Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by the mutation of either the TSC1 or TSC2 genes and characterized by the presence of benign cortical lesions known as cortical tubers. A large proportion of patients with TSC exhibit neurological symptoms including epilepsy and intellectual disability, and a further 50% meet the diagnostic criteria for Autism. However, the appearance of this broad spectrum of neurologic manifestations does not always correlate with the neuroanatomical defects common to TSC, suggesting the possibility of underlying functional defects affecting neural development in TSC patients. Here we have utilized neural progenitor cells (NPCs) capable of fully differentiating into neurons, which carry a heterozygous TSC2 mutation generated from patient-derived induced pluripotent stem cells (iPSCs) to investigate TSC cellular and molecular phenotypes. In these cell lines we observe that TSC2 +/ NPCs exhibit changes in cell signaling along the Akt/mTORC1 signaling axis. This pathway is classically affected in TSC, with elevated pS6 and decreased phospho-Akt levels known as neuropathological hallmarks in knockout mouse models and studies of abnormal human tissue. Consistent with these previous findings we observed a decrease in the activity of AKT as measured by levels of phospho-AKT Thr308 and Ser473. Evidence of increased mTORC1 signaling was seen in one patient, but not another, suggesting TSC2 heterozygosity may produce modest signaling changes near a functional threshold for generating a molecular phenotype in NPCs. TSC2 heterozygous NPCs also exhibited a reduced capacity to produce neurons in vitro, suggesting that neural development may be impacted in TSC. Moreover, this phenotype was reproduced upon AKT inhibition of control NPC lines, but was unaffected under treatment with rapamycin, suggesting that AKT signaling may play a more prominent role in mediating the neurodevelopmental defects of TSC than previously thought.
Advisors/Committee Members: D'Arcangelo, Gabriella (chair), Hart, Ronald (internal member), Dreyfus, Cheryl (internal member), Roko-Rasin, Mladen (internal member), Jacinto, Estella (outside member), School of Graduate Studies.
Subjects/Keywords: Tuberous sclerosis
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APA (6th Edition):
Zucco, Avery, 1. (2018). The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/59301/
Chicago Manual of Style (16th Edition):
Zucco, Avery, 1990-. “The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex.” 2018. Doctoral Dissertation, Rutgers University. Accessed January 15, 2021.
https://rucore.libraries.rutgers.edu/rutgers-lib/59301/.
MLA Handbook (7th Edition):
Zucco, Avery, 1990-. “The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex.” 2018. Web. 15 Jan 2021.
Vancouver:
Zucco, Avery 1. The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex. [Internet] [Doctoral dissertation]. Rutgers University; 2018. [cited 2021 Jan 15].
Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/59301/.
Council of Science Editors:
Zucco, Avery 1. The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex. [Doctoral Dissertation]. Rutgers University; 2018. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/59301/
Oregon State University
2.
Edwards, Thomas Allen.
A clinical and genetic study of tuberous sclerosis.
Degree: MS, Genetics, 1972, Oregon State University
URL: http://hdl.handle.net/1957/45487
► Tuberous sclerosis is a serious heritable human disorder that involves many organ systems. It was first recognized as a disease entity over a century ago.…
(more)
▼ Tuberous sclerosis is a serious heritable human disorder
that involves many organ systems. It was first recognized as a
disease entity over a century ago. Its mode of transmission in
familial cases has been fairly well established to be that of a single
gene locus autosomal dominant trait. However, the majority of
cases reported in the medical literature have been found to be of
de novo mutational origin. The finding of a high proportion of these
sporadic cases was confirmed in the present study and is consistent
with the markedly lowered fertility of affected individuals.
The population of the Oregon State Fairview Hospital and
Training Center, the state institution for the mentally retarded, was
investigated relative to the incidence of patients with
tuberous sclerosis
and the clinical, radiological and genetic aspects of the ten
propositi were evaluated. Two parents of the ten index cases were
found to be affected with the disease thereby bringing the: total of
ascertained cases to 12. This number of affected residents represents
an incidence in Oregon of about 1 per 175,000 and this estimate
is probably lower than the actual frequency of
tuberous sclerosis in the
state. Yet, this incidence is approximately comparable to that
reported in several published reviews of
tuberous sclerosis in other
countries.
Physical and radiographic examinations were accomplished for
the index cases. All available relatives (77 percent of living relatives)
of the propositi were examined and photographed. Skull x-rays of the
two affected parents revealed intracranial calcifications typical of the
disorder.
A majority of the ten propositi exhibited dermatological legions
such as a typical facial rash, fibromata of the fingers and toes,
"sharkskin-like" plaques, depigmented areas and cafe-au-lait spots.
All affected individuals were found to display x-ray abnormalities
with intracranial calcifications being the most frequently found radiographic
lesion.
Implications derived from this study regarding genetic counseling
of affected persons and their families are discussed with emphasis
on the importance of a thorough genetic history, complete medical
examination of the patient and of close relatives; and, where indicated,
selected x-rays of the affected person and relatives considered to be
possible carriers of the trait. The wide spectrum of expressivity for this condition must be borne in mind when carrying out a genetic
analysis.
With the present limited knowledge regarding the causation of
"spontaneous point mutations" and the lack of effective measures to
prevent such de novo genetic aberrations, it is not feasible to diminish
the frequency of sporadic cases of
tuberous sclerosis. On the
other hand, correct diagnosis and appropriate genetic counseling
should allow a significant decrease in the transmission of this trait
to the progeny of affected persons and should permit reassurance of
relatives of sporadic cases regarding the risk of recurrence in these
families. However, the usual…
Advisors/Committee Members: Bogart, Ralph (advisor).
Subjects/Keywords: Tuberous sclerosis
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APA (6th Edition):
Edwards, T. A. (1972). A clinical and genetic study of tuberous sclerosis. (Masters Thesis). Oregon State University. Retrieved from http://hdl.handle.net/1957/45487
Chicago Manual of Style (16th Edition):
Edwards, Thomas Allen. “A clinical and genetic study of tuberous sclerosis.” 1972. Masters Thesis, Oregon State University. Accessed January 15, 2021.
http://hdl.handle.net/1957/45487.
MLA Handbook (7th Edition):
Edwards, Thomas Allen. “A clinical and genetic study of tuberous sclerosis.” 1972. Web. 15 Jan 2021.
Vancouver:
Edwards TA. A clinical and genetic study of tuberous sclerosis. [Internet] [Masters thesis]. Oregon State University; 1972. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1957/45487.
Council of Science Editors:
Edwards TA. A clinical and genetic study of tuberous sclerosis. [Masters Thesis]. Oregon State University; 1972. Available from: http://hdl.handle.net/1957/45487
Boston University
3.
Zgoda, Molly Flynn.
Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytes.
Degree: MS, Medical Sciences, 2019, Boston University
URL: http://hdl.handle.net/2144/36741
► Bone is a highly dynamic organ system comprised of various cell types that are constantly working to maintain the health and stability of bone. The…
(more)
▼ Bone is a highly dynamic organ system comprised of various cell types that are constantly working to maintain the health and stability of bone. The main cells involved are the osteoblasts that form bone, the osteoclasts that degrade bone, and the osteocytes that act as sensors of the microenvironment and coordinate a response. An imbalance of the interactions between the cell types can potentially result in pathological states in bone at the microscopic level that can then affect the entire skeleton. Moreover, a number of genetic mutations can also lead to pathogenic changes in bone. An example of such is the development of sclerotic bone lesions in patients with the disease
tuberous sclerosis complex.
Tuberous sclerosis complex, or TSC, is an autosomal dominant disorder affecting approximately 1.5 million people worldwide. It is caused by a mutation in one of the genes encoding either member of the TSC1-TSC2 complex. Molecularly, TSC1-TSC2 negatively regulate the mechanistic target of rapamycin (mTOR) kinase in the mutli-protein complex mTORC1. Activation of mTORC1 leads to an upregulation of protein synthesis and cell growth.
Tuberous sclerosis patients are heterozygous for TSC1 or TSC2, and post-natal loss of the second allele results in the development of multiple, benign, tumor-like hamartomas in various organ systems, most notably affecting the brain, kidneys, lungs, skin, and heart. Additionally, CT scans of patients reveal multiple loci of dense, compact bone termed sclerotic bone lesions. The bone lesions were most commonly seen in the posterior elements of the vertebrae and while they are asymptomatic, a remarkably high frequency of patients express them.
To further investigate and better understand the mechanisms of
tuberous sclerosis complex in bone, we analyzed a mouse model with heterozygous deletion in Tsc2. Initial examination showed the Tsc2+/- mice recapitulated tumors in various organ systems, most notably the kidney, and presented bone lesions in the pelvis and elements of the vertebrae. To further investigate the mechanism driving the disease state, we used a Cre driver thought to be specific for osteoclast (Cathepsin K-Cre, or Ctsk-Cre) to selectively delete Tsc2. Cathepsin K-Cre; Tsc2fl/fl mice exhibit a remarkably high bone mass. This study examined three specific aspects of this high bone mass phenotype. First, we sought to verify that the increased bone mass caused by Ctsk-Cre driven Tsc2 deletion was dependent on mTORC1 upregulation. This was done by generating Ctsk-Cre;Tsc2fl/fl mice lacking Raptor, a mTORC1 component essential for function. Next, we investigated the cell of origin driving the increase bone density by utilizing additional Cre drivers specific for osteoclasts and osteocytes. Additionally, we used radiation chimeras to assess if donated wild type cells could rescue the observed phenotype. We lastly explored the role of a secreted signaling molecule, CTHRC1, that has been proposed as a candidate to mediate osteoclast-osteoblast interaction, in…
Advisors/Committee Members: Franzblau, Carl (advisor).
Subjects/Keywords: Medicine; Bone; mTOR; Tuberous sclerosis
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APA (6th Edition):
Zgoda, M. F. (2019). Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytes. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/36741
Chicago Manual of Style (16th Edition):
Zgoda, Molly Flynn. “Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytes.” 2019. Masters Thesis, Boston University. Accessed January 15, 2021.
http://hdl.handle.net/2144/36741.
MLA Handbook (7th Edition):
Zgoda, Molly Flynn. “Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytes.” 2019. Web. 15 Jan 2021.
Vancouver:
Zgoda MF. Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytes. [Internet] [Masters thesis]. Boston University; 2019. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/2144/36741.
Council of Science Editors:
Zgoda MF. Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytes. [Masters Thesis]. Boston University; 2019. Available from: http://hdl.handle.net/2144/36741
Vanderbilt University
4.
Armour, Eric Andrew.
Dysregulated mTOR signaling and tissue-specific phenotypes in Tuberous Sclerosis Complex.
Degree: PhD, Cell and Developmental Biology, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/14546
► Tuberous Sclerosis Complex (TSC) is a multi-organ hamartomatous disease caused by loss of function mutations in either the TSC1 or TSC2 genes. Despite involvement of…
(more)
▼ Tuberous Sclerosis Complex (TSC) is a multi-organ hamartomatous disease caused by loss of function mutations in either the TSC1 or TSC2 genes. Despite involvement of multiple organs such as the kidneys, lungs, and skin, neurological aspects are usually the most severe due to a very high prevalence of cognitive impairment, autism and epilepsy. The protein products of TSC1 and TSC2, hamartin and tuberin respectively, regulate the mTOR kinase signaling pathway. Current models of TSC propose that hamartoma formation is secondary to a loss of heterozygosity at either the TSC1 or TSC2 loci, and subsequent hyperactivation of mTOR Complex 1 (mTORC1). In this dissertation I explore the underlying mechanisms of organ specific pathogenesis in TSC.
In the first half of my dissertation, I demonstrate that loss of Tsc1 in the distal convoluted tubule of the kidney results in cystogenesis. Cyst formation in these kidneys is due to a mTORC1 but not mTORC2 dependent process. I then show that cystic changes in these kidneys may be due to ciliary defects.
While a loss of heterozygosity has clearly been reported in the kidney and other organ system, second hit mutations in neural lesions have only rarely been identified. Thus, to begin to define the role of the heterozygosity of TSC1 or TSC2 during the pathogenesis of TSC in the brain, we generated induced pluripotent stem cells (iPSC) from patients with TSC. Deep sequencing of these patents revealed that all of our patient derived lines are heterozygous for TSC2 mutations. I then provide evidence that these heterozygous iPSCs are abnormal with increased cell survival and enhanced maintenance of pluripotency. These changes may be due to slight changes in mTORC1 signaling.
The work presented in this dissertation increases our understanding of the tissue specific phenotypes and underlying mechanisms of TSC pathogenesis. This research may lead to the identification of new therapeutic targets for TSC and associated comorbidities.
Advisors/Committee Members: Alfred L. George (committee member), Maureen A. Gannon (committee member), Wenbiao Chen (committee member), Kevin C. Ess (committee member), Chin Chiang (Committee Chair).
Subjects/Keywords: TSC; pluripotency; Tuberous Sclerosis; cilia; cystogenesis; mTOR
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APA (6th Edition):
Armour, E. A. (2013). Dysregulated mTOR signaling and tissue-specific phenotypes in Tuberous Sclerosis Complex. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14546
Chicago Manual of Style (16th Edition):
Armour, Eric Andrew. “Dysregulated mTOR signaling and tissue-specific phenotypes in Tuberous Sclerosis Complex.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/14546.
MLA Handbook (7th Edition):
Armour, Eric Andrew. “Dysregulated mTOR signaling and tissue-specific phenotypes in Tuberous Sclerosis Complex.” 2013. Web. 15 Jan 2021.
Vancouver:
Armour EA. Dysregulated mTOR signaling and tissue-specific phenotypes in Tuberous Sclerosis Complex. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/14546.
Council of Science Editors:
Armour EA. Dysregulated mTOR signaling and tissue-specific phenotypes in Tuberous Sclerosis Complex. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/14546
University College London (University of London)
5.
Woodward, Karen Jane.
Characterisation of the TSC1 candidate region on human chromosome 9q34.
Degree: PhD, 1995, University College London (University of London)
URL: https://discovery.ucl.ac.uk/id/eprint/10103069/
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283661
► Tuberous sclerosis (TSC) is an autosomal dominant disorder with clinical symptoms ranging from minor skin lesions to more serious manifestations such as mental retardation and…
(more)
▼ Tuberous sclerosis (TSC) is an autosomal dominant disorder with clinical symptoms ranging from minor skin lesions to more serious manifestations such as mental retardation and seizures. Linkage analysis established heterogeneity and assigned genes to 9q34 (TSC1) and 16p13.3 (TSC2). Detection of TSC-associated deletions on 16p13.3 refined the localisation of the gene and TSC2 has now been identified. Meiotic recombination events in TSC families have defined a consensus candidate region for TSC1 between D9S149 and D9S114, but further refinement gives conflicting positions for the gene. A positional cloning strategy has been applied to characterise the TSC 1 candidate region and identify the gene. Radiation hybrids retaining markers from the target interval were characterised and used as a resource for region specific DNA. The clones isolated plus ones from other sources were confirmed to map to 9q34 by FISH. Localisations were refined by using three lymphoblastoid cell lines with translocations breakpoints within 9q34, thereby subdividing the band into 4 intervals. A total of 32 loci from 28 contigs, and 43 anonymous contigs were mapped enabling a FISH map to be constructed. Cosmids mapping to the TSC1 candidate region were subsequently screened for transcribed sequences by exon amplification. The initial study led to the identification VAV2, a good candidate for TSC1. It was followed by more extensive analysis of 6 contigs mapping to the same FISH interval as D9S149 and D9S114. A total of 171 putative exons were cloned, 48 potentially different products were sequenced and 34 were inferred to be authentic exons. A subset from 4 contigs were confirmed to be conserved sequences by cross-species hybridisation and cDNA clones were isolated and partially characterised. The exons and cDNAs isolated are important resources for construction of a 9q34 transcription map and may facilitate identification of the TSC1 gene.
Subjects/Keywords: 572.8; Tuberous sclerosis
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APA (6th Edition):
Woodward, K. J. (1995). Characterisation of the TSC1 candidate region on human chromosome 9q34. (Doctoral Dissertation). University College London (University of London). Retrieved from https://discovery.ucl.ac.uk/id/eprint/10103069/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283661
Chicago Manual of Style (16th Edition):
Woodward, Karen Jane. “Characterisation of the TSC1 candidate region on human chromosome 9q34.” 1995. Doctoral Dissertation, University College London (University of London). Accessed January 15, 2021.
https://discovery.ucl.ac.uk/id/eprint/10103069/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283661.
MLA Handbook (7th Edition):
Woodward, Karen Jane. “Characterisation of the TSC1 candidate region on human chromosome 9q34.” 1995. Web. 15 Jan 2021.
Vancouver:
Woodward KJ. Characterisation of the TSC1 candidate region on human chromosome 9q34. [Internet] [Doctoral dissertation]. University College London (University of London); 1995. [cited 2021 Jan 15].
Available from: https://discovery.ucl.ac.uk/id/eprint/10103069/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283661.
Council of Science Editors:
Woodward KJ. Characterisation of the TSC1 candidate region on human chromosome 9q34. [Doctoral Dissertation]. University College London (University of London); 1995. Available from: https://discovery.ucl.ac.uk/id/eprint/10103069/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283661
University College London (University of London)
6.
Gillett, Godfrey Tregelles.
Use of irradiation hybrids in gene mapping on human chromosome 11.
Degree: PhD, 1999, University College London (University of London)
URL: https://discovery.ucl.ac.uk/id/eprint/10111089/
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322187
► The original objective of the work described in this thesis was the development of genetic and physical mapping resources on human chromosome 11q23 in order…
(more)
▼ The original objective of the work described in this thesis was the development of genetic and physical mapping resources on human chromosome 11q23 in order to facilitate the positional cloning of a putative locus for Tuberous Sclerosis in that region of the chromosome. To this end I constructed a panel of high dose irradiation hybrids using as a starting point a human-hamster somatic cell hybrid retaining chromosome 11 as its only human material. Forty-seven of the hybrids were characterised in detail by molecular methods and also in some cases by fluorescent in situ hybridisation. A promising hybrid (Jol2) was subcloned further to derive a hybrid containing only 11q23 as its human component. By this time it had become clear that most cases of Tuberous Sclerosis can be accounted for either by mutations at TSCl (9q34) or TSC2 (16p13) and that a locus on chromosome 11, if it exists, must account for very few cases of the disease, making an attempt at positional cloning impractical. The hybrids were therefore used in collaboration with others for the development of region specific probes, some of which were directly useful in the mapping and ultimately the cloning of genes causing ataxia telangiectasia (11q23) and multiple endocrine neoplasia type 1 (11q13). In particular I was able to show that Alu-PCR products from well-characterised hybrids could be used in a rapid and reliable way to obtain regionally defined cosmid clones from the gridded chromosome 11 library available from ICRF. In the course of this work I made use of these and other hybrids to provide new chromosomal localisations for several other genes including those coding for cofilins (CFL1 and CFL2), a fucosyl transferase (FUT4), a retinoic receptor (RXRB) and a mitochondrial NAD-dependent malic enzyme.
Subjects/Keywords: 572.8; Tuberous Sclerosis
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APA (6th Edition):
Gillett, G. T. (1999). Use of irradiation hybrids in gene mapping on human chromosome 11. (Doctoral Dissertation). University College London (University of London). Retrieved from https://discovery.ucl.ac.uk/id/eprint/10111089/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322187
Chicago Manual of Style (16th Edition):
Gillett, Godfrey Tregelles. “Use of irradiation hybrids in gene mapping on human chromosome 11.” 1999. Doctoral Dissertation, University College London (University of London). Accessed January 15, 2021.
https://discovery.ucl.ac.uk/id/eprint/10111089/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322187.
MLA Handbook (7th Edition):
Gillett, Godfrey Tregelles. “Use of irradiation hybrids in gene mapping on human chromosome 11.” 1999. Web. 15 Jan 2021.
Vancouver:
Gillett GT. Use of irradiation hybrids in gene mapping on human chromosome 11. [Internet] [Doctoral dissertation]. University College London (University of London); 1999. [cited 2021 Jan 15].
Available from: https://discovery.ucl.ac.uk/id/eprint/10111089/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322187.
Council of Science Editors:
Gillett GT. Use of irradiation hybrids in gene mapping on human chromosome 11. [Doctoral Dissertation]. University College London (University of London); 1999. Available from: https://discovery.ucl.ac.uk/id/eprint/10111089/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322187
University of Windsor
7.
Davis, Gordon Omar.
Regulation of Tuberin in Cell Fate Acquisition within Developing Neural Tissues.
Degree: MS, Biological Sciences, 2012, University of Windsor
URL: https://scholar.uwindsor.ca/etd/5424
► Inhibition or misregulation of the tumour suppressor protein Tuberin is known to cause the benign tumour disorder Tuberous Sclerosis, involving developmental defects in many…
(more)
▼ Inhibition or misregulation of the tumour suppressor protein Tuberin is known to cause the benign tumour disorder
Tuberous Sclerosis, involving developmental defects in many organ systems including the central nervous system. Data supports that appropriate control of Tuberin levels may play an essential role in the regulation of neural fate decisions. Hence, this work investigates the regulation of Tuberin through neural development both in vitro, using SH-SY5Y and RN33B neuronal precursor cells, and in vivo using murine neural tissues. We demonstrate that Tuberin expression and activity are significantly down-regulated during neuronal differentiation in vitro, and during aging in vivo, in a cell and tissue specific manner. We have developed tools needed to address the essentiality of Tuberin in neural differentiation in vitro and to begin to dissect the molecular pathways affected. Understanding how Tuberin is regulated through neural development is necessary in understanding the developmental defects and pathologies associated with
Tuberous Sclerosis.
Advisors/Committee Members: Lisa A Porter, Elizabeth Fidalgo da Silva.
Subjects/Keywords: Cell Fate; Neural Development; Tuberin; Tuberous Sclerosis
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APA (6th Edition):
Davis, G. O. (2012). Regulation of Tuberin in Cell Fate Acquisition within Developing Neural Tissues. (Masters Thesis). University of Windsor. Retrieved from https://scholar.uwindsor.ca/etd/5424
Chicago Manual of Style (16th Edition):
Davis, Gordon Omar. “Regulation of Tuberin in Cell Fate Acquisition within Developing Neural Tissues.” 2012. Masters Thesis, University of Windsor. Accessed January 15, 2021.
https://scholar.uwindsor.ca/etd/5424.
MLA Handbook (7th Edition):
Davis, Gordon Omar. “Regulation of Tuberin in Cell Fate Acquisition within Developing Neural Tissues.” 2012. Web. 15 Jan 2021.
Vancouver:
Davis GO. Regulation of Tuberin in Cell Fate Acquisition within Developing Neural Tissues. [Internet] [Masters thesis]. University of Windsor; 2012. [cited 2021 Jan 15].
Available from: https://scholar.uwindsor.ca/etd/5424.
Council of Science Editors:
Davis GO. Regulation of Tuberin in Cell Fate Acquisition within Developing Neural Tissues. [Masters Thesis]. University of Windsor; 2012. Available from: https://scholar.uwindsor.ca/etd/5424
Universiteit Utrecht
8.
Roccio, M.
The small GTPase Rheb in insulin and nutrient signaling.
Degree: 2007, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/19063
► The insulin-signaling pathway controls different aspects of cell proliferation, survival, growth and metabolism. The coordinated regulation of cell growth with the availability of nutrients is…
(more)
▼ The insulin-signaling pathway controls different aspects of cell proliferation, survival, growth and metabolism. The coordinated regulation of cell growth with the availability of nutrients is a major requirement for all eukaryotic organisms for proper development and prevention of tumor formation. This signaling network has lately received attention from the field of basic cancer research due to the increasing evidence that mutations in its components are at the base of cancer or tumor-prone syndromes. Moreover, the possibility of targeting the players in this process with anticancer drugs like rapamycin, increased the interest from the clinical point of view. The identification of Rheb as a component of the insulin pathway, acting downstream of PI3K and PKB and upstream of the ser/thr kinase mTOR, revealed the connection between these two signaling cascades. mTOR acts as master switch between anabolic and catabolic cellular processes, regulating cell growth. Its regulation by nutrient availability has been known for long, however the mechanism by which hormones like insulin and growth factors control its activity, became evident when Rheb was identified as an activator of mTOR, directly regulated by these cues.
Subjects/Keywords: Geneeskunde; insulin; tuberous sclerosis; protein synthesis; rapamycin; Rheb; mTOR
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APA (6th Edition):
Roccio, M. (2007). The small GTPase Rheb in insulin and nutrient signaling. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/19063
Chicago Manual of Style (16th Edition):
Roccio, M. “The small GTPase Rheb in insulin and nutrient signaling.” 2007. Doctoral Dissertation, Universiteit Utrecht. Accessed January 15, 2021.
http://dspace.library.uu.nl:8080/handle/1874/19063.
MLA Handbook (7th Edition):
Roccio, M. “The small GTPase Rheb in insulin and nutrient signaling.” 2007. Web. 15 Jan 2021.
Vancouver:
Roccio M. The small GTPase Rheb in insulin and nutrient signaling. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2007. [cited 2021 Jan 15].
Available from: http://dspace.library.uu.nl:8080/handle/1874/19063.
Council of Science Editors:
Roccio M. The small GTPase Rheb in insulin and nutrient signaling. [Doctoral Dissertation]. Universiteit Utrecht; 2007. Available from: http://dspace.library.uu.nl:8080/handle/1874/19063
Universiteit Utrecht
9.
Jansen, F.E.
Identification of epileptogenic tubers in patients with tuberous sclerosis complex.
Degree: 2007, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/20560
► Identification of epileptogenic tubers in patients with tuberous sclerosis complex Tuberous sclerosis complex (TSC) is associated with epilepsy and mental retardation. The principal aim of…
(more)
▼ Identification of epileptogenic tubers in patients with tuberous sclerosis complex Tuberous sclerosis complex (TSC) is associated with epilepsy and mental retardation. The principal aim of this thesis was to identify epileptogenic tuber(s) enabling the selection of patients for epilepsy surgery. In addition we analysed possible determinants of cognitive functioning in patients with TSC. Genotype (different TSC1 and TSC2 mutations, tuber status and epilepsy variables were related to cognitive functioning. We found a statistically significantly lower cognition index in patients with a TSC2 mutation, but the overlap was considerable. A higher proportion of brain volume occupied by tubers was related to a lower intelligence equivalent and tended to be related to a lower cognition index. In a multivariable analysis age at seizure onset was identified as the only independent predictor of cognitive functioning. To date there is no strategy available to prevent seizure onset, prompting adequate treatment as soon as seizures occur. Epilepsy surgery is often not considered in patients with TSC as epileptogenicity from one tuber to another is feared. We found that patients with consistent localisation of interictal epileptiform EEG activity are characterised by an older at seizure onset, less often infantile spasms or generalised tonic clonic seizures, and a higher intelligence equivalent when compared to patients with inconsistent foci. Before epilepsy surgery can be performed the identification of the epileptogenic tuber is a prerequisite. Both magnetoencephalography (MEG) and diffusion weighted MRI (DWI) contributed significantly to the selection of TSC patients for epilepsy surgery. We found that MEG sources were closer to presumed epileptogenic tubers (mean distance of 13.8 mm) than EEG sources (mean distance of 24.7 mm) and MEG more often revealed unifocal epileptiform activity. Further, apparent diffusion coefficient (ADC) maps of four epileptogenic tubers (mean 1099 mm/s, SD 35.0) were statistically significantly higher than that of 18 non-epileptogenic tubers (mean 926 mm/s, SD 69.4) and of 16 regions of normal appearing cortex (mean 784 mm/s, SD 61.7). A systematic literature study on seizure outcome after epilepsy surgery in patients with TSC and multi-drug resistant epilepsy revealed that seizure freedom was achieved in 101 (57%) of the 177 included patients, from 25 studies. Seizure frequency was reduced by > 90% in another 32 patients (18%). Moderate or severe intellectual disability (defined as IQ <70) (RR 1.8; 95% CI 1.2- 2.8) and the presence of tonic seizures (RR 1.7; 95 % CI 1.2- 2.4) were related to seizure recurrence. Subsequently, we evaluated presurgical investigations in 25 Dutch TSC patients with multi-drug resistant epilepsy in whom epilepsy surgery was considered. Suitable candidates were identified by one region of seizure onset, or sufficient seizure burden. Six patients underwent epilepsy surgery. Four of these patients had excellent outcome. Differential accumulation of hamartin and tuberin in…
Subjects/Keywords: Geneeskunde; tuberous sclerosis; epilepsy; source localisation; epilepsy surgery; cognition
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APA (6th Edition):
Jansen, F. E. (2007). Identification of epileptogenic tubers in patients with tuberous sclerosis complex. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/20560
Chicago Manual of Style (16th Edition):
Jansen, F E. “Identification of epileptogenic tubers in patients with tuberous sclerosis complex.” 2007. Doctoral Dissertation, Universiteit Utrecht. Accessed January 15, 2021.
http://dspace.library.uu.nl:8080/handle/1874/20560.
MLA Handbook (7th Edition):
Jansen, F E. “Identification of epileptogenic tubers in patients with tuberous sclerosis complex.” 2007. Web. 15 Jan 2021.
Vancouver:
Jansen FE. Identification of epileptogenic tubers in patients with tuberous sclerosis complex. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2007. [cited 2021 Jan 15].
Available from: http://dspace.library.uu.nl:8080/handle/1874/20560.
Council of Science Editors:
Jansen FE. Identification of epileptogenic tubers in patients with tuberous sclerosis complex. [Doctoral Dissertation]. Universiteit Utrecht; 2007. Available from: http://dspace.library.uu.nl:8080/handle/1874/20560
10.
山田, 博.
The ominous sequence in patients with tuberous sclerosis complex.
Degree: 博士(医学), 2016, Oita University / 大分大学
URL: http://hdl.handle.net/10559/15587
► Background: The clinical phenotypes and their severity in patients with tuberous sclerosis complex can be quite variable and are sometimes never determined simply by the…
(more)
▼ Background: The clinical phenotypes and their severity in patients with tuberous sclerosis complex can be quite variable and are sometimes never determined simply by the primary mutation. These make clinically selecting appropriate treatments and predicting disease outcome difficult. In this report, the prognostic ominous sequence was evaluated in association with clinical manifestations and gene mutations. Methods: The patients were classified by each renal lesion of angiomyolipomas and polycystic disease. The other clinical manifestations and outcomes of epilepsy, mental retardation, facial angiofibromas, subependymal giant cell astrocytoma, cortical tubers were reviewed and each gene mutations were analyzed in seven unrelated patients. Results: Two patients with multiple and large proliferative renal angiomyolipoma showed poor clinical outcome than the patients with other renal lesions. These patients presented with progressively proliferative facial angiofibroma, West syndrome, Lennox–Gastaut syndrome, severe mental retardation, subependymal giant cell astrocytoma and they were affected by TSC2 gene mutations. Conclusion: The sequence of progressively proliferative renal angiomyolipoma, facial angiofibroma, West syndrome and TSC2 gene mutations might be prognostic ominous factors.
Subjects/Keywords: Tuberous sclerosis complex; TSC1; TSC2; Angiomyolipomas; West syndrome
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APA (6th Edition):
山田, . (2016). The ominous sequence in patients with tuberous sclerosis complex. (Thesis). Oita University / 大分大学. Retrieved from http://hdl.handle.net/10559/15587
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
山田, 博. “The ominous sequence in patients with tuberous sclerosis complex.” 2016. Thesis, Oita University / 大分大学. Accessed January 15, 2021.
http://hdl.handle.net/10559/15587.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
山田, 博. “The ominous sequence in patients with tuberous sclerosis complex.” 2016. Web. 15 Jan 2021.
Vancouver:
山田 . The ominous sequence in patients with tuberous sclerosis complex. [Internet] [Thesis]. Oita University / 大分大学; 2016. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/10559/15587.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
山田 . The ominous sequence in patients with tuberous sclerosis complex. [Thesis]. Oita University / 大分大学; 2016. Available from: http://hdl.handle.net/10559/15587
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
11.
Armstrong, Laura Craig.
Modeling Tuberous Sclerosis Complex
Using Patient-Derived Cells.
Degree: PhD, Cell and Developmental Biology, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/14161
► Tuberous Sclerosis Complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2…
(more)
▼ Tuberous Sclerosis Complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. TSC causes refractory epilepsy and intellectual disability but the pathogenesis of the neurological symptoms is not understood. Identifying when and in what cell types mutations in TSC1 or TSC2 lead to neurological dysfunction is the first step to better and more targeted treatments. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprograming plasmid containing a shRNA against TP53. Loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. Further, we show that homozygous loss of TSC2 leads to increased mTORC1 in neural progenitors and impaired neural progenitor formation. These results support the contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming.
Advisors/Committee Members: Aaron Bowman (committee member), Charles Hong (committee member), Andrea Page McCaw (committee member), David Miller (committee member), Kevin Ess (Committee Chair).
Subjects/Keywords: p53; induced pluripotent stem cells; tuberous sclerosis complex; mTOR
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APA (6th Edition):
Armstrong, L. C. (2017). Modeling Tuberous Sclerosis Complex
Using Patient-Derived Cells. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14161
Chicago Manual of Style (16th Edition):
Armstrong, Laura Craig. “Modeling Tuberous Sclerosis Complex
Using Patient-Derived Cells.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/14161.
MLA Handbook (7th Edition):
Armstrong, Laura Craig. “Modeling Tuberous Sclerosis Complex
Using Patient-Derived Cells.” 2017. Web. 15 Jan 2021.
Vancouver:
Armstrong LC. Modeling Tuberous Sclerosis Complex
Using Patient-Derived Cells. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/14161.
Council of Science Editors:
Armstrong LC. Modeling Tuberous Sclerosis Complex
Using Patient-Derived Cells. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/14161
Harvard University
12.
Lewis, William.
Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism.
Degree: Doctor of Medicine, 2014, Harvard University
URL: http://etds.lib.harvard.edu/hms/admin/view/45
;
http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407607
► Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease caused by loss of the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) genes. Neurologic symptoms are…
(more)
▼ Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease caused by loss of the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) genes. Neurologic symptoms are common and varied in TSC and include epilepsy and behavioral conditions like autism spectrum disorders (ASD). Between 17 and 61% of children with TSC exhibit symptoms of ASD.
The purpose of this study was to investigate a potential correlate of poor neurological outcome in TSC by assessing the integrity of brain language pathways and the relationship to ASD.
42 patients with TSC and 42 age-matched control subjects were scanned with advanced diffusion-weighted MRI. White matter language pathways were identified with a validated automatic method and analyzed for microstructural characteristics, including fractional anisotropy (FA) and mean diffusivity (MD). Well-defined white matter pathways in the brain are characterized by high FA and low MD. During normal development, brain white matter pathways increase in FA and decrease in MD.
Out of 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD showed a small decrease in FA of the arcuate fasciculus compared to control subjects, and TSC patients with ASD had much lower FA than both control subjects and TSC patients without ASD. Similarly, while TSC patients without ASD had only a small increase in MD compared to control subjects in the arcuate fasciculus, TSC patients with ASD had much higher MD than control subjects and TSC patients without ASD.
A new method for assessing the microstructure of young patients showed similar results with decreased compactness in language pathways of TSC patients with ASD. Another new method designed to better analyze regions with crossing pathways showed modifications in language pathway microstructure that correlated with ASD diagnosis in the TSC patients. Preliminary analysis of neuropsychiatric data also showed a trend toward an association of arcuate fasciculus MD with verbal IQ, although the result was not significant after multiple comparisons correction.
It remains unclear why some patients with TSC develop ASD, while others have better language outcomes. Our results suggest that aberrant development of language pathways may act as a marker for poor neurological outcome in TSC patients. The impaired microstructure in language pathways of TSC patients may be responsible for the development of ASD, although prospective studies examining the development of language pathways and subsequent ASD diagnosis in this patient population remain essential. It is also possible that a primary problem with language leads to decreased use and subsequent poor development of language pathways. Early diagnosis of ASD is crucial for improving the outcomes of affected children.
Subjects/Keywords: Tuberous sclerosis complex; autism spectrum disorders; brain magnetic resonance imaging; language
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APA (6th Edition):
Lewis, W. (2014). Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism. (Doctoral Dissertation). Harvard University. Retrieved from http://etds.lib.harvard.edu/hms/admin/view/45 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407607
Chicago Manual of Style (16th Edition):
Lewis, William. “Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism.” 2014. Doctoral Dissertation, Harvard University. Accessed January 15, 2021.
http://etds.lib.harvard.edu/hms/admin/view/45 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407607.
MLA Handbook (7th Edition):
Lewis, William. “Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism.” 2014. Web. 15 Jan 2021.
Vancouver:
Lewis W. Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism. [Internet] [Doctoral dissertation]. Harvard University; 2014. [cited 2021 Jan 15].
Available from: http://etds.lib.harvard.edu/hms/admin/view/45 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407607.
Council of Science Editors:
Lewis W. Changes in Language Pathways in Tuberous Sclerosis Complex Patients with Autism. [Doctoral Dissertation]. Harvard University; 2014. Available from: http://etds.lib.harvard.edu/hms/admin/view/45 ; http://nrs.harvard.edu/urn-3:HUL.InstRepos:12407607
University College London (University of London)
13.
Jeganathan, Dharini.
Identification and analysis of mutations in the TSC1 gene.
Degree: PhD, 2000, University College London (University of London)
URL: https://discovery.ucl.ac.uk/id/eprint/10100389/
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326099
► Tuberous Sclerosis Complex (TSC) an autosomal dominant disorder which may cause many abnormalities including skin rashes, renal lesions, seizures, learning disability and behavioural problems is…
(more)
▼ Tuberous Sclerosis Complex (TSC) an autosomal dominant disorder which may cause many abnormalities including skin rashes, renal lesions, seizures, learning disability and behavioural problems is caused by mutations in either of two genes TSC1 or TSC2. This thesis focuses on the analysis of the recently cloned TSC1 gene. Mutation screening revealed that virtually all TSC1 mutations are predicted to truncate the protein product. This provided a model system for the investigation of nonsense mediated mRNA decay (NMD), an enigmatic surveillance mechanism that may offer the cell some protection against such "dominant-negative" nonsense mutations. Analysis of lymphoblastoid cell lines in seven TSC1 patients showed a striking reduction of the mutant transcript compared to the normal transcript in five cases. Coding and newly identified 3' UTR polymorphisms in TSC1 were utilised in the development of an assay to investigate imbalance between allelic transcripts in TSC patients. In doing so, it was demonstrated that the observed reduction of allele-specific RNA in TSC1 patients was not in general the result of exon skipping but the result of lower levels of the whole mutant transcript caused by the premature termination codon (PTC). In addition, the normal range of allelic imbalance in control samples was established. Based on these findings, the correct identification of six out of seven TSC1 patients tested blind from a panel of TSC1 and TSC2 patients was achieved with no false positives. Fresh blood samples were obtained from a panel of TSC patients to evaluate this approach as a diagnostic tool. Here, the discrimination between alleles was less sensitive with RNA obtained directly from blood samples than from lymphoblastoid lines. It was also found that an alternative transcript lacking exon 5 of TSC1 was a prominent feature of RNA from fresh lymphocytes. A further series of experiments on lymphoblastoid cell lines gave rise to three main findings of general interest. Firstly, the position of the mutation within the gene could not be used to predict the extent of NMD. Secondly, patients with the same mutation, whether or not known to be related, appeared to have comparable levels of NMD implying that the variation in severity seen within the same family is unlikely to be the result of variation in NMD. Thirdly, exposure of the cells in culture to puromycin, a translational inhibitor, reduced the imbalance between 'normal' and 'mutant' transcript. This suggested that NMD depends on translation or translational associated machinery, where its control may be determined directly by the mutation or by another factor yet to be identified. Overall, the findings suggest that from a mutation screening point of view, NMD may be a useful tool where cell-lines are available. Inspection of the literature shows that NMD is the rule rather than the exception for mutations which cause PTCs. Thus, in the future, with the advent of a dense SNP map of transcribed regions, it may be possible to take a similar approach to the assessment of…
Subjects/Keywords: 572.8; Tuberous sclerosis complex
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APA ·
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APA (6th Edition):
Jeganathan, D. (2000). Identification and analysis of mutations in the TSC1 gene. (Doctoral Dissertation). University College London (University of London). Retrieved from https://discovery.ucl.ac.uk/id/eprint/10100389/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326099
Chicago Manual of Style (16th Edition):
Jeganathan, Dharini. “Identification and analysis of mutations in the TSC1 gene.” 2000. Doctoral Dissertation, University College London (University of London). Accessed January 15, 2021.
https://discovery.ucl.ac.uk/id/eprint/10100389/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326099.
MLA Handbook (7th Edition):
Jeganathan, Dharini. “Identification and analysis of mutations in the TSC1 gene.” 2000. Web. 15 Jan 2021.
Vancouver:
Jeganathan D. Identification and analysis of mutations in the TSC1 gene. [Internet] [Doctoral dissertation]. University College London (University of London); 2000. [cited 2021 Jan 15].
Available from: https://discovery.ucl.ac.uk/id/eprint/10100389/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326099.
Council of Science Editors:
Jeganathan D. Identification and analysis of mutations in the TSC1 gene. [Doctoral Dissertation]. University College London (University of London); 2000. Available from: https://discovery.ucl.ac.uk/id/eprint/10100389/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326099
14.
MacRae, Rebecca.
Characterizing Cognitive, Treatment, and Epilepsy Outcomes in a Sub-Population of Patients With Tuberous Sclerosis Complex and Spasms: Patients With Focal Seizures Preceding Spasms.
Degree: Doctor of Medicine, 2018, Harvard University
URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973534
► Purpose: To characterize the cognitive outcomes, epilepsy, and treatment response, specifically to vigabatrin, of tuberous sclerosis complex (TSC) patients with focal seizures prior to the…
(more)
▼ Purpose: To characterize the cognitive outcomes, epilepsy, and treatment
response, specifically to vigabatrin, of tuberous sclerosis complex (TSC) patients with focal seizures prior to the onset of infantile spasms (IS) or epileptic spasms (ES) compared with patients with spasm onset prior to other seizure types.
Methods: The authors retrospectively reviewed the charts of 185 TSC patients
with a history of IS or ES and epilepsy. Medical records were assessed for clinical information about gender, age of spasm onset, clinical descriptions, concomitant seizure type, age of concomitant seizure onset, treatment, treatment response, and genetic analyses.
Results: Of the 541 patients with TSC, 185 were diagnosed with IS or ES. A subset of 14 patients received a diagnosis of focal seizure onset prior to spasms onset. A subset of 36 patients received a diagnosis of spasms onset prior to focal seizure onset. The records for 135 patients did not contain detailed documentation regarding the specific onset of spasms and/or focal seizures. Patients with focal seizure preceding spasm onset tend to have lower rates of normal IQ/cognition (7 vs 28%) and higher rates of intellectual disability (93 vs 72%) with a trend of more severe level of intellectual disability (moderate > mild/borderline/normal). They tend to have a less effective response to vigabatrin treatment of spasms (58 vs 82%). These patients also develop significantly higher rates of refractory epilepsy (77% vs 32%).
Conclusions: Compared with TSC patients who present with spasm preceding focal seizure onset, patients with TSC who present with focal seizure preceding spasm onset tend to have more a more severe clinical profile with respect to neurocognitive outcome, response to vigabatrin, and development of refractory epilepsy.
Scholarly Project
Subjects/Keywords: tuberous sclerosis; spasms; vigabatrin
…patients seen in
the Herscot Center for Tuberous Sclerosis Complex at the Massachusetts General… …Acknowledgements
This study was supported by the Carol and James Herscot Center for Tuberous Sclerosis… …Tuberous sclerosis complex: linking growth and energy
signaling pathways with human disease… …diagnosis of tuberous sclerosis complex in the United States. Genet Med. 9,
88-100.
Camposano SE… …Influence of seizures on early development in tuberous sclerosis complex.
Epilepsy & Behavior…
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APA ·
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APA (6th Edition):
MacRae, R. (2018). Characterizing Cognitive, Treatment, and Epilepsy Outcomes in a Sub-Population of Patients With Tuberous Sclerosis Complex and Spasms: Patients With Focal Seizures Preceding Spasms. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973534
Chicago Manual of Style (16th Edition):
MacRae, Rebecca. “Characterizing Cognitive, Treatment, and Epilepsy Outcomes in a Sub-Population of Patients With Tuberous Sclerosis Complex and Spasms: Patients With Focal Seizures Preceding Spasms.” 2018. Doctoral Dissertation, Harvard University. Accessed January 15, 2021.
http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973534.
MLA Handbook (7th Edition):
MacRae, Rebecca. “Characterizing Cognitive, Treatment, and Epilepsy Outcomes in a Sub-Population of Patients With Tuberous Sclerosis Complex and Spasms: Patients With Focal Seizures Preceding Spasms.” 2018. Web. 15 Jan 2021.
Vancouver:
MacRae R. Characterizing Cognitive, Treatment, and Epilepsy Outcomes in a Sub-Population of Patients With Tuberous Sclerosis Complex and Spasms: Patients With Focal Seizures Preceding Spasms. [Internet] [Doctoral dissertation]. Harvard University; 2018. [cited 2021 Jan 15].
Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973534.
Council of Science Editors:
MacRae R. Characterizing Cognitive, Treatment, and Epilepsy Outcomes in a Sub-Population of Patients With Tuberous Sclerosis Complex and Spasms: Patients With Focal Seizures Preceding Spasms. [Doctoral Dissertation]. Harvard University; 2018. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41973534
15.
Slegtenhorst, Marjon.
Tuberous Sclerosis Complex I: gene identification and characterisation.
Degree: 1998, Erasmus University Medical Center
URL: http://hdl.handle.net/1765/13665
► textabstractThis thesis describes the identification and the characterisation of the gene involved in tuberous sclerosis complex (TSC) on chromosome 9 (TSCl). For tItis purpose we…
(more)
▼ textabstractThis thesis describes the identification and the characterisation of the gene involved in
tuberous sclerosis complex (TSC) on chromosome 9 (TSCl). For tItis purpose we used the
positional cloning approach, a strategy by which many other disease genes, including the
TSC2 gene on chromosome 16, have been isolated in the past years. The identification of the
TSCI gene has taken 10 years of search and involved the cloning of the entire 1.5 Mb
candidate region.
Tuberous sclerosis is characterised by the widespread development of distinctive tumours
(hamartomas) in many different tissues, and a broad phenotypic spectnl1u which lllay often
include disturbed mental function, renal problems and dermatological abnormalities. TSC has
an estimated prevalence of 1/6000 and occurs when either one of the TSCI or TSC2 tumour
suppressor genes is inactivated. Mutations in the TSCI and TSC2 genes cause a velY similar
clinical phenotype, suggesting that both genes play a closely related role in a still
undetenllined biological process.
Evidence for linkage between TSC and markers on cluomosome 9q34 had already been
found in 1987. A consensus TSCI interval was defined in 1994, spanning approximately 1.5
Mb of genontic DNA. Refining the critical interval in affected individuals proved to be
difficult, because of conflicting recombinant data in TSC families.
Subjects/Keywords: gene identification; tuberous sclerosis
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APA (6th Edition):
Slegtenhorst, M. (1998). Tuberous Sclerosis Complex I: gene identification and characterisation. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/13665
Chicago Manual of Style (16th Edition):
Slegtenhorst, Marjon. “Tuberous Sclerosis Complex I: gene identification and characterisation.” 1998. Doctoral Dissertation, Erasmus University Medical Center. Accessed January 15, 2021.
http://hdl.handle.net/1765/13665.
MLA Handbook (7th Edition):
Slegtenhorst, Marjon. “Tuberous Sclerosis Complex I: gene identification and characterisation.” 1998. Web. 15 Jan 2021.
Vancouver:
Slegtenhorst M. Tuberous Sclerosis Complex I: gene identification and characterisation. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 1998. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1765/13665.
Council of Science Editors:
Slegtenhorst M. Tuberous Sclerosis Complex I: gene identification and characterisation. [Doctoral Dissertation]. Erasmus University Medical Center; 1998. Available from: http://hdl.handle.net/1765/13665
University of Windsor
16.
Dare-Shih, Jessica Morgan.
IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS.
Degree: MS, Biological Sciences, 2016, University of Windsor
URL: https://scholar.uwindsor.ca/etd/5633
► The cell cycle is a highly dynamic and phasic process controlling cell growth, DNA duplication, and successful division into two daughter cells. Regulation of this…
(more)
▼ The cell cycle is a highly dynamic and phasic process controlling cell growth, DNA duplication,
and successful division into two daughter cells. Regulation of this process is key to avoiding errors and
activation of cell death. Tumour suppressor proteins, such as Tuberin, and cell cycle proteins, such as
Cyclin B1 are highly important in co-ordinating adequate cell growth and properly timed cell division,
respectively. It is known that mutation, truncation, and misregulation of the Tuberin protein can result in
diseases like
Tuberous Sclerosis and cancer. This study demonstrated that a clinically relevant Tuberin
truncation, S664Δ, increases cellular proliferation and exhibits aberrant localization compared to wildtype
Tuberin. Additionally, our study showed that S664Δ is able to bind Cyclin B1, which may derange
proper co-ordination of the G2/M transition. Findings here may have clinical implications towards better
understanding the progression of disease involving misregulated Tuberin.
Advisors/Committee Members: Porter, Lisa, Fidalgo da Silva, Elizabeth.
Subjects/Keywords: cell cycle; cyclin B1; localization; mitosis; tuberous sclerosis
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APA (6th Edition):
Dare-Shih, J. M. (2016). IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS. (Masters Thesis). University of Windsor. Retrieved from https://scholar.uwindsor.ca/etd/5633
Chicago Manual of Style (16th Edition):
Dare-Shih, Jessica Morgan. “IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS.” 2016. Masters Thesis, University of Windsor. Accessed January 15, 2021.
https://scholar.uwindsor.ca/etd/5633.
MLA Handbook (7th Edition):
Dare-Shih, Jessica Morgan. “IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS.” 2016. Web. 15 Jan 2021.
Vancouver:
Dare-Shih JM. IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS. [Internet] [Masters thesis]. University of Windsor; 2016. [cited 2021 Jan 15].
Available from: https://scholar.uwindsor.ca/etd/5633.
Council of Science Editors:
Dare-Shih JM. IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS. [Masters Thesis]. University of Windsor; 2016. Available from: https://scholar.uwindsor.ca/etd/5633
University of Arkansas
17.
Sivakumar, Sowmya.
Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb.
Degree: MS, 2018, University of Arkansas
URL: https://scholarworks.uark.edu/etd/2948
► Protein-protein interactions are vital in maintaining proper function and homeostasis in cells. Some signaling pathways are regulated by G-proteins that work like switches to…
(more)
▼ Protein-protein interactions are vital in maintaining proper function and homeostasis in cells. Some signaling pathways are regulated by G-proteins that work like switches to activate and deactivate pathways. Mutations in these proteins, their effectors or the interaction between proteins may cause dysregulation of signals that can lead to many diseases.
Rheb, Ras homology enriched in brain, is a Ras family GTPase that is vital in regulation of the mTOR (mammalian target of rapamycin) pathway that signals cell proliferation and growth. Due to the low intrinsic GTPase activity of Rheb, a GTPase activating protein (GAP),
Tuberous Sclerosis Complex 2 (TSC2) down regulates Rheb by enhancing its GTPase activity. Currently, very little information is available about TSC2 structures and the molecular details of the interaction between the two proteins. We explored various biochemical and biophysical information of Rheb-TSC2 interaction. In addition, we characterized the stability of the variant, TSC2-218 (D74A), using a 218 amino acid truncated construct of TSC2, and the effects of the single point mutation on the interactions with Rheb. In comparison to the WT, the D74A variant showed to maintain protein stability (thermal and chemical), an increase in secondary (alpha helical) structure, binding and GAP activity towards Rheb.
Advisors/Committee Members: Paul Adams, Colin Heyes, Suresh Thallapuranam.
Subjects/Keywords: Ras; Rheb; TSC2; Tuberous Sclerosis; Biochemistry; Biophysics; Cell Biology
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APA (6th Edition):
Sivakumar, S. (2018). Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb. (Masters Thesis). University of Arkansas. Retrieved from https://scholarworks.uark.edu/etd/2948
Chicago Manual of Style (16th Edition):
Sivakumar, Sowmya. “Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb.” 2018. Masters Thesis, University of Arkansas. Accessed January 15, 2021.
https://scholarworks.uark.edu/etd/2948.
MLA Handbook (7th Edition):
Sivakumar, Sowmya. “Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb.” 2018. Web. 15 Jan 2021.
Vancouver:
Sivakumar S. Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb. [Internet] [Masters thesis]. University of Arkansas; 2018. [cited 2021 Jan 15].
Available from: https://scholarworks.uark.edu/etd/2948.
Council of Science Editors:
Sivakumar S. Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb. [Masters Thesis]. University of Arkansas; 2018. Available from: https://scholarworks.uark.edu/etd/2948
University of Arkansas
18.
Morris, Kyla Marie Morinini.
Biochemical and Biophysical Studies of Novel Features of Ras-related Protein Interactions.
Degree: MS, 2013, University of Arkansas
URL: https://scholarworks.uark.edu/etd/1002
► The Ras superfamily of G-proteins are of great research interest for structure-function relationships among proteins as they act as molecular switches in the regulation…
(more)
▼ The Ras superfamily of G-proteins are of great research interest for structure-function relationships among proteins as they act as molecular switches in the regulation of various biochemical reactions in the cell. They are regulated by protein-protein interactions targeted to the highly flexible switch regions. Mutations in G-proteins or their effectors may cause alterations in structure and/or function that can lead to overactivity.
The Ras-related protein Cell division cycle 42 (Cdc42) is important in regulating cell-signaling processes. The T35A mutation in Cdc42 leads to a decrease in flexibility of the Switch I region responsible for effector binding. The kinetics of the intrinsic GTP hydrolysis reaction were compared for Cdc42 (WT and T35A) in the absence and presence of a peptide derivative of PAK21 activated kinase (PBD46). The mutation does not affect the intrinsic GTP hydrolysis rate of Cdc42, but binding with PBD46 is altered by the mutation; in the presence of PBD46, GTP hydrolysis is completely inhibited for Cdc42 WT while partial recovery of GTP hydrolysis for Cdc42 T35A was observed in the presence of PBD46. The data obtained lead us to propose two slowly interconverting conformational states of Cdc42 T35A, both able to hydrolyze GTP, but one that shows a weakened affinity for PBD46.
Ras homolog enriched in brain (Rheb) is a member of the Ras superfamily of proteins known to regulate cell growth and proliferation by signaling the mammalian target of rapamycin (mTOR) pathway. The
Tuberous Sclerosis Complex 2 protein (TSC2) regulates Rheb by functioning as a GTPase activating protein (GAP). At present, very little is known about the molecular features of the Rheb-TSC2 protein interaction. We present biochemical and biophysical data on the interaction of Rheb with TSC2 WT, using a shorter, 218 amino acid GTPase derivative of TSC2 (TSC2-218), as well as with the mutant TSC2-218 K114A, to characterize the TSC2-218 constructs and their GAP activity towards Rheb. A decrease in secondary structure as well as a loss of GAP activity is seen in the K114A mutant compared to WT.
Advisors/Committee Members: Paul Adams, Suresh Thallapuranam, Roger Koeppe.
Subjects/Keywords: Pure sciences; Biological sciences; Protein; Ras; Tuberous sclerosis; Biochemistry; Biophysics
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APA (6th Edition):
Morris, K. M. M. (2013). Biochemical and Biophysical Studies of Novel Features of Ras-related Protein Interactions. (Masters Thesis). University of Arkansas. Retrieved from https://scholarworks.uark.edu/etd/1002
Chicago Manual of Style (16th Edition):
Morris, Kyla Marie Morinini. “Biochemical and Biophysical Studies of Novel Features of Ras-related Protein Interactions.” 2013. Masters Thesis, University of Arkansas. Accessed January 15, 2021.
https://scholarworks.uark.edu/etd/1002.
MLA Handbook (7th Edition):
Morris, Kyla Marie Morinini. “Biochemical and Biophysical Studies of Novel Features of Ras-related Protein Interactions.” 2013. Web. 15 Jan 2021.
Vancouver:
Morris KMM. Biochemical and Biophysical Studies of Novel Features of Ras-related Protein Interactions. [Internet] [Masters thesis]. University of Arkansas; 2013. [cited 2021 Jan 15].
Available from: https://scholarworks.uark.edu/etd/1002.
Council of Science Editors:
Morris KMM. Biochemical and Biophysical Studies of Novel Features of Ras-related Protein Interactions. [Masters Thesis]. University of Arkansas; 2013. Available from: https://scholarworks.uark.edu/etd/1002
University of California – Irvine
19.
Schmunk, Galina.
IP3-Mediated Ca2+ Signaling Deficit in Monogenic and Sporadic Forms of Autism Spectrum Disorders.
Degree: Biomedical Sciences, 2017, University of California – Irvine
URL: http://www.escholarship.org/uc/item/0x50k43t
► Autism spectrum disorder (ASD) affects 2% of children and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of…
(more)
▼ Autism spectrum disorder (ASD) affects 2% of children and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing evidence supports a role of disrupted Ca2+ signaling in ASD. I developed and applied a high-throughput fluorometric imaging plate reader (FLIPR) assay to monitor agonist-evoked Ca2+ signals in human primary skin fibroblasts. My results indicate that IP3 -mediated Ca2+ release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic, as well as rare syndromic forms of ASD. This was apparent in Ca2+ signals evoked by G protein-coupled receptors and by photoreleased IP3 at the levels of both global and local elementary Ca2+ events, suggesting fundamental defects in IP3R channel activity in ASD. Given the ubiquitous involvement of IP3R-mediated Ca2+ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, I further expanded my findings to a murine model of FXS. Activation of the IP3 cascade via plasma membrane metabotropic receptors did not reveal any Ca2+ signaling deficits in neurons from mice with the FMR1 gene deletion. Glial cells from FXS mice did not demonstrate any sizable difference in response to GPCR activation, or IP3 UV flash uncaging as compared with wild type. Finally, mouse fibroblasts from FXS mice assayed with the high-throughput screen FLIPR, analogous to what was used on the human skin fibroblasts, did not reveal any difference in the IP3-mediated Ca2+ release compared with wild type mice. These findings highlight divergence between animal models and human conditions, and show inadequacy of the murine model in studying the effect of the FMR1 gene mutation on IP3 signaling cascade. In conclusion, my findings suggest that deficits in IP3-mediated Ca2+ signaling represent a convergent function shared across the spectrum of autistic disorders – whether caused by rare highly penetrant mutations or sporadic forms – and hold promise as a biomarker for diagnosis and novel drug discovery. This work also highlights potential pharmaceutical targets, and identifies Ca2+ screening in human skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.
Subjects/Keywords: Neurosciences; Biophysics; autism; autism spectrum disorders; calcium; fragile x; ip3 receptor; tuberous sclerosis
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APA ·
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CSE |
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APA (6th Edition):
Schmunk, G. (2017). IP3-Mediated Ca2+ Signaling Deficit in Monogenic and Sporadic Forms of Autism Spectrum Disorders. (Thesis). University of California – Irvine. Retrieved from http://www.escholarship.org/uc/item/0x50k43t
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Schmunk, Galina. “IP3-Mediated Ca2+ Signaling Deficit in Monogenic and Sporadic Forms of Autism Spectrum Disorders.” 2017. Thesis, University of California – Irvine. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/0x50k43t.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Schmunk, Galina. “IP3-Mediated Ca2+ Signaling Deficit in Monogenic and Sporadic Forms of Autism Spectrum Disorders.” 2017. Web. 15 Jan 2021.
Vancouver:
Schmunk G. IP3-Mediated Ca2+ Signaling Deficit in Monogenic and Sporadic Forms of Autism Spectrum Disorders. [Internet] [Thesis]. University of California – Irvine; 2017. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/0x50k43t.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Schmunk G. IP3-Mediated Ca2+ Signaling Deficit in Monogenic and Sporadic Forms of Autism Spectrum Disorders. [Thesis]. University of California – Irvine; 2017. Available from: http://www.escholarship.org/uc/item/0x50k43t
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Ottawa
20.
Delaney, Sean Phillip.
Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis
.
Degree: 2019, University of Ottawa
URL: http://hdl.handle.net/10393/39810
► The multisystemic tumors characteristic of the monogenic neoplastic diseases, tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), share common signaling aberrations upon the loss of heterozygosity…
(more)
▼ The multisystemic tumors characteristic of the monogenic neoplastic diseases, tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), share common signaling aberrations upon the loss of heterozygosity in either the TSC1 or TSC2 genes. However, their physical manifestations are vastly different and can generally be classified as being either neurological (TSC) or mesenchymal (TSC & LAM; referred to herein as LAM for simplicity) in origin. In this study, I present a comprehensive stem cell model of LAM utilizing multiple TSC2 knockout (TSC2-/-) pluripotent stem cell lines differentiated to the putative cell of origin for mesenchymal tumors, neural crest cells (NCCs). TSC2-/- NCCs faithfully recapitulate LAM phenotypes and temporal RNA-seq analysis of neural and neural crest differentiation was performed to model disease pathogenesis. Analysis revealed immediate activation of stress response signaling resulting in protein aggregation and lysosome and autophagosome accumulation upon neuralization in TSC2-/- cells. This resulted in acute and lasting effects specific to neural progenitor cells (NPCs), that are transient and ameliorated in NCCs. These lineage-specific effects resulted in selective sensitization of NPCs to cell death via proteasome inhibition, suggesting a potential therapeutic avenue for neurological TSC, but not LAM. Thus, a genome-wide CRISPR knockout screen was performed in TSC2-/- NCCs. Analysis of synthetic lethal genes reveals pathways previously targeted for LAM, but provides gene-level resolution to the vulnerable nodes within these pathways. Importantly, 18 novel gene targets were identified that display synthetic lethality to TSC2-/- cells with high specificity. 3 genes within this list were targetable using commercially available small molecule inhibitors, one of which, FGFR1, shows highly selective lethal targeting of TSC2-/- NCCs. Importantly, this model system, paired with the expansive resource of transcriptomic and synthetic lethal data, serves as a foundation for the development of next generation treatment strategies for LAM, and potentially the entire spectrum of TSC manifestations.
Subjects/Keywords: Disease modeling;
Tuberous sclerosis;
Lymphangioleiomyomatosis;
Neoplasm;
mTOR signaling;
CRISPR;
Stem cell;
Neural crest;
TSC2
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Delaney, S. P. (2019). Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/39810
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Delaney, Sean Phillip. “Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis
.” 2019. Thesis, University of Ottawa. Accessed January 15, 2021.
http://hdl.handle.net/10393/39810.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Delaney, Sean Phillip. “Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis
.” 2019. Web. 15 Jan 2021.
Vancouver:
Delaney SP. Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis
. [Internet] [Thesis]. University of Ottawa; 2019. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/10393/39810.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Delaney SP. Modeling and Therapeutic Development for the Tuberous Sclerosis Related Neoplasm Lymphangioleiomyomatosis
. [Thesis]. University of Ottawa; 2019. Available from: http://hdl.handle.net/10393/39810
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – San Francisco
21.
Young, David Matthew.
Altered Ultrasonic Vocalizations in a Tuberous Sclerosis Mouse Model of Autism.
Degree: Neuroscience, 2010, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/65m6881t
► Tuberous sclerosis (TSC) is an autosomal dominant neurocutaneous disease notable for its high co-morbidity with autism in human patients. Studies of mouse models of tuberous…
(more)
▼ Tuberous sclerosis (TSC) is an autosomal dominant neurocutaneous disease notable for its high co-morbidity with autism in human patients. Studies of mouse models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother-pup social interaction during or prior to the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2+/- dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups' USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pup's interaction with its mother strongly influences its vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this mouse model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.
Subjects/Keywords: Neurobiology; Behavioral Sciences; Biology, Bioinformatics; autism; communication; maternal care; mouse model; tuberous sclerosis; vocalizations
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Young, D. M. (2010). Altered Ultrasonic Vocalizations in a Tuberous Sclerosis Mouse Model of Autism. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/65m6881t
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Young, David Matthew. “Altered Ultrasonic Vocalizations in a Tuberous Sclerosis Mouse Model of Autism.” 2010. Thesis, University of California – San Francisco. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/65m6881t.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Young, David Matthew. “Altered Ultrasonic Vocalizations in a Tuberous Sclerosis Mouse Model of Autism.” 2010. Web. 15 Jan 2021.
Vancouver:
Young DM. Altered Ultrasonic Vocalizations in a Tuberous Sclerosis Mouse Model of Autism. [Internet] [Thesis]. University of California – San Francisco; 2010. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/65m6881t.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Young DM. Altered Ultrasonic Vocalizations in a Tuberous Sclerosis Mouse Model of Autism. [Thesis]. University of California – San Francisco; 2010. Available from: http://www.escholarship.org/uc/item/65m6881t
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – San Francisco
22.
Hsiao, Jeffrey Chieh.
Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET.
Degree: Biomedical Imaging, 2018, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/5rj4p3mh
► The diagnosis and management of the phenotypically heterogeneous and progressive disorders tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) is a significant clinical challenge owing to…
(more)
▼ The diagnosis and management of the phenotypically heterogeneous and progressive disorders tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) is a significant clinical challenge owing to a lack of disease specific biomarkers. Because the genetic mutations in TSC1 and/or TSC2 characteristic of TSC and LAM activate mTORC1 signaling, we hypothesized that disease burden could be measured with PET using 89Zr-transferrin (Tf). Toward this goal, we show that spontaneous renal cystadenomas arising in a genetically engineered mouse model heterozygous for Tsc2 were readily detectable with 89Zr-Tf PET. Moreover, subcutaneous implants of TSC and LAM cell line models consistently harbored high avidity for 89Zr-Tf in vivo. Deeper mechanistic studies showed that transferrin receptor expression and Tf biology were mTORC1 regulated in TSC and LAM models. Finally, the early treatment effects of clinically approved and experimental systemic therapies for TSC and LAM were interpretable using 89Zr-Tf PET. In summary, these data advance a translatable molecular imaging strategy that may be capable of detecting and longitudinally monitoring whole body TSC and LAM disease burden.
Subjects/Keywords: Medical imaging; Chemistry; Pharmaceutical sciences; Lymphangioleiomyomatosis; mTORC1 Signaling; PET Imaging; Transferrin; Tuberous Sclerosis Complex; Zirconium
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APA (6th Edition):
Hsiao, J. C. (2018). Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/5rj4p3mh
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Hsiao, Jeffrey Chieh. “Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET.” 2018. Thesis, University of California – San Francisco. Accessed January 15, 2021.
http://www.escholarship.org/uc/item/5rj4p3mh.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hsiao, Jeffrey Chieh. “Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET.” 2018. Web. 15 Jan 2021.
Vancouver:
Hsiao JC. Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET. [Internet] [Thesis]. University of California – San Francisco; 2018. [cited 2021 Jan 15].
Available from: http://www.escholarship.org/uc/item/5rj4p3mh.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hsiao JC. Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET. [Thesis]. University of California – San Francisco; 2018. Available from: http://www.escholarship.org/uc/item/5rj4p3mh
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of South Carolina
23.
Biederman, Diane L.
Reproductive-Aged Adults Diagnosed with Tuberous Sclerosis Complex (TSC): Understanding of Clinical Variability, Perceived Disease Burden, and Reproductive Decision-Making.
Degree: Degree ofMSin Genetic Counseling, Genetic Counseling, 2019, University of South Carolina
URL: https://scholarcommons.sc.edu/etd/5228
► Tuberous Sclerosis Complex (TSC) is a highly variable autosomal dominant multisystem disorder characterized by the growth of benign tumors, epilepsy, and TSC- associated neuropsychiatric…
(more)
▼ Tuberous Sclerosis Complex (TSC) is a highly variable autosomal dominant multisystem disorder characterized by the growth of benign tumors, epilepsy, and TSC- associated neuropsychiatric disorders (TAND). There is a high level of clinical variability, even within the same family. While reproductive decisions always carry a level of uncertainty, individuals with highly variable genetic conditions like TSC must consider both the chance of passing on the condition and the uncertain clinical presentation. There is currently no literature on factors influencing reproductive decisions of adults with TSC. To address this gap in understanding, we conducted an exploratory mixed-methods survey utilizing an anonymous online questionnaire to assess study participants’: 1) familiarity with the symptoms of TSC, 2) understanding of the risk of passing on TSC, 3) perceived disease burden/quality of life, and 4) family planning considerations. A total of 175 individuals aged 18-45 who were diagnosed with TSC were included in the final data set. Participants were highly familiar with symptoms of TSC with an average symptom knowledge score of 86.64%. Cortical tubers, angiofibromas, angiomyolipomas, and seizures were recognized as symptoms of TSC by more than 95% of participants. Lymphangioleiomyomatosis (LAM) was the least recognized symptom (75.29%), with females being statistically more likely to recognize the symptom than males. Most participants (85.96%) were aware of the 50% recurrence risk of TSC. Perceived disease burden was low with 58.58% viewing themselves as mildly or very mildly affected. Our disease burden/quality of life instrument found that a majority of participants reported that they felt different from those around them, that they were frustrated by their symptoms, that their symptoms made them anxious, and that they thought about their TSC at least some of the time. Sleep disturbance and pain caused by TSC were also common. However, a majority of participants felt like they were in control of their lives, felt good about their social life, felt comfortable meeting new people, and felt they had the support they needed. Around 60% of our study population was considering having future children with the average desired number of children equaling 2.25. Reproductive methods being considered included traditional conception (52.94%), adoption (45.10%), donor gametes or embryos (17.64%), and preimplantation genetic diagnosis ([PGD], 50.00%). Thematic analysis showed desire for biological children, personal health, desire to not pass on TSC, financial concerns, and fertility issues were major factors in choice of reproductive method. Interest in prenatal testing was high with 67.44% stating they would test a hypothetical future pregnancy. Thematic analysis showed being informed, considering termination of pregnancy, and accepting whatever happens as major themes for individuals’ interest or lack thereof in prenatal testing. While more studies are needed, the results of this survey will help genetic counselors address…
Advisors/Committee Members: Debera Zvejnieks.
Subjects/Keywords: Genetics and Genomics; Tuberous Sclerosis Complex; TSC; tumors; epilepsy; TSC- associated neuropsychiatric disorders; TAND; Lymphangioleiomyomatosis
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APA ·
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APA (6th Edition):
Biederman, D. L. (2019). Reproductive-Aged Adults Diagnosed with Tuberous Sclerosis Complex (TSC): Understanding of Clinical Variability, Perceived Disease Burden, and Reproductive Decision-Making. (Thesis). University of South Carolina. Retrieved from https://scholarcommons.sc.edu/etd/5228
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Biederman, Diane L. “Reproductive-Aged Adults Diagnosed with Tuberous Sclerosis Complex (TSC): Understanding of Clinical Variability, Perceived Disease Burden, and Reproductive Decision-Making.” 2019. Thesis, University of South Carolina. Accessed January 15, 2021.
https://scholarcommons.sc.edu/etd/5228.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Biederman, Diane L. “Reproductive-Aged Adults Diagnosed with Tuberous Sclerosis Complex (TSC): Understanding of Clinical Variability, Perceived Disease Burden, and Reproductive Decision-Making.” 2019. Web. 15 Jan 2021.
Vancouver:
Biederman DL. Reproductive-Aged Adults Diagnosed with Tuberous Sclerosis Complex (TSC): Understanding of Clinical Variability, Perceived Disease Burden, and Reproductive Decision-Making. [Internet] [Thesis]. University of South Carolina; 2019. [cited 2021 Jan 15].
Available from: https://scholarcommons.sc.edu/etd/5228.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Biederman DL. Reproductive-Aged Adults Diagnosed with Tuberous Sclerosis Complex (TSC): Understanding of Clinical Variability, Perceived Disease Burden, and Reproductive Decision-Making. [Thesis]. University of South Carolina; 2019. Available from: https://scholarcommons.sc.edu/etd/5228
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pennsylvania
24.
Tsai, Victoria.
The Role of TSC2 and Deptor in Fetal Cortical Development.
Degree: 2012, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/714
► Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that results form mutations in the TSC1 or TSC2 genes. TSC is a multisystem hamartoma…
(more)
▼ Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that results form mutations in the TSC1 or TSC2 genes. TSC is a multisystem hamartoma syndrome with manifestations in the brain, heart, lungs, kidney, skin and eyes. Neurologically, TSC patients may exhibit severe epilepsy, cognitive disabilities, and autism spectrum disorders. TSC1 and TSC2 proteins form a heterodimeric complex that serves to inhibit mammalian target of rapamycin (mTOR) signaling pathway. TSC1 and TSC2 receive activating or inhibitory signaling from multiple inputs including growth factors, insulin signaling, energy and amino acid levels, and proinflammatory pathways, and then integrate those signals to regulate the activity of mTOR. mTOR signaling plays a critical role in regulating cell growth, transcription, translation, and autophagy. Animal models have shed light on certain features of TSC, but failed to recapitulate the disease completely and currently further research is under way to better understand this devastating disorder. To date, mTOR signaling hyperactivation has been demonstrated in TSC tubers at postnatal time points, thus we set out to study the profile of mTOR activation in the fetal brain. We utilized both mouse neural progenitors in vitro and developing brain in vivo systems to understand the effects of Tsc1 and Tsc2 during brain development. Furthermore, after the identification of a new mTOR regulatory protein Deptor (DEPDC6 gene), which inhibits the mTORC1 and mTORC2 signaling pathways similar to TSC1-TSC protein complex, we examined its role in brain development. We found that Deptor shRNA knockdown results in mTORC1 and mTORC2 activation in vitro as well as abnormal migration in vivo. Our results show that mTOR signaling pathway could be the common pathway on which TSC1, TSC2, and DEPTOR converge and exert their effects on brain development. These results suggest mTOR signaling and its downstream effectors could be targets for therapeutic treatment during embryogenesis and could potentially prevent abnormal brain development.
Subjects/Keywords: brain development; deptor; epilepsy; mtor; tsc2; tuberous sclerosis complex; Developmental Biology; Neuroscience and Neurobiology
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APA (6th Edition):
Tsai, V. (2012). The Role of TSC2 and Deptor in Fetal Cortical Development. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/714
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Tsai, Victoria. “The Role of TSC2 and Deptor in Fetal Cortical Development.” 2012. Thesis, University of Pennsylvania. Accessed January 15, 2021.
https://repository.upenn.edu/edissertations/714.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Tsai, Victoria. “The Role of TSC2 and Deptor in Fetal Cortical Development.” 2012. Web. 15 Jan 2021.
Vancouver:
Tsai V. The Role of TSC2 and Deptor in Fetal Cortical Development. [Internet] [Thesis]. University of Pennsylvania; 2012. [cited 2021 Jan 15].
Available from: https://repository.upenn.edu/edissertations/714.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Tsai V. The Role of TSC2 and Deptor in Fetal Cortical Development. [Thesis]. University of Pennsylvania; 2012. Available from: https://repository.upenn.edu/edissertations/714
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Michigan
25.
Yang, Qian.
mTOR regulation.
Degree: PhD, Pure Sciences, 2007, University of Michigan
URL: http://hdl.handle.net/2027.42/126861
► The mammalian target of rapamycin (mTOR) is an evolutionally conserved protein kinase and a central cell growth controller. It integrates both extracellular and intracellular signals,…
(more)
▼ The mammalian target of rapamycin (mTOR) is an evolutionally conserved protein kinase and a central cell growth controller. It integrates both extracellular and intracellular signals, including nutrients, growth factors, energy levels and cellular stresses to regulate a wide array of vital cellular processes, such as transcription, translation, cytoskeleton modification, autophagy and apoptosis. Dysregulation of mTOR is involved in many human diseases, including cancer, cardiovascular disease, autoimmunity, and metabolic disorder. Therefore, understanding of mTOR function and regulation is essential for developing therapeutics that will improve quality of life. Recent discoveries in the mTOR research field are highlighted by the identification of mTOR-associated proteins with which mTOR assemble different complexes that have distinct physiological functions. So far, two mTOR complexes have been identified, termed as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is sensitive to rapamycin and mainly regulates cell growth, whereas mTORC2 is insensitive to rapamycin and regulates cell structure and survival. The tumor suppressor genes,
Tuberous Sclerosis Complex 1 and 2 ( TSC1 and 2), and the small GTPase, Ras-homolog enriched in brain (Rheb), have been identified as the major upstream regulators of mTORC1. mTORC2 has been placed downstream of PI3K regulation, but the regulatory mechanism remains unknown. In this thesis, I summarize my research in the past few years in regards to two aspects. First, I identified a new mTORC2 subunit, Sin1, which is important for mTORC2 assembly and functions. Second, I examined Rheb effects on mTORC2, and concluded that it indirectly suppresses mTORC2 activity. My research only covers a fraction of mTOR biology, and thus its contribution is limited. There are many important questions that remain to be answered, which will inspire further scientific inquiries.
Advisors/Committee Members: Guan, Kun-Liang (advisor).
Subjects/Keywords: Gtpase; Gtpases; Mtor; Pi3k; Regulation; Rheb; Tuberous Sclerosis Complex
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APA (6th Edition):
Yang, Q. (2007). mTOR regulation. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/126861
Chicago Manual of Style (16th Edition):
Yang, Qian. “mTOR regulation.” 2007. Doctoral Dissertation, University of Michigan. Accessed January 15, 2021.
http://hdl.handle.net/2027.42/126861.
MLA Handbook (7th Edition):
Yang, Qian. “mTOR regulation.” 2007. Web. 15 Jan 2021.
Vancouver:
Yang Q. mTOR regulation. [Internet] [Doctoral dissertation]. University of Michigan; 2007. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/2027.42/126861.
Council of Science Editors:
Yang Q. mTOR regulation. [Doctoral Dissertation]. University of Michigan; 2007. Available from: http://hdl.handle.net/2027.42/126861
Texas Medical Center
26.
Reith, Rachel Michelle.
CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM.
Degree: PhD, 2012, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/266
► Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form…
(more)
▼ Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either
TSC1 or
TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the
Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). These mice exhibit progressive Purkinje cell degeneration.
Since loss of Purkinje cells is a well-reported postmortem finding in patients with ASD, we conducted a series of behavior tests to assess if Tsc2f/-;Cre mice displayed autistic-like deficits. Using the three chambered social choice assay, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. Tsc2f/-;Cre mice also demonstrated increased repetitive behavior as assessed with marble burying activity. Altogether, these results demonstrate that loss of
Tsc2 in Purkinje cells in a haploinsufficient background lead to behavioral deficits that are characteristic of human autism. Therefore, Purkinje cells loss and/or dysfunction may be an important link between TSC and ASD.
Additionally, we have examined some of the cellular mechanisms resulting from mutations in
Tsc2 leading to Purkinje cell death. Loss of
Tsc2 led to upregulation of mTORC1 and increased cell size. As a consequence of increased protein synthesis, several cellular stress pathways were upregulated. Principally, these included altered calcium signaling, oxidative stress, and ER stress. Likely as a consequence of ER stress, there was also upregulation of ubiquitin and autophagy.
Excitingly, treatment with an mTORC1 inhibitor, rapamycin attenuated mTORC1 activity and prevented Purkinje cell death by reducing of calcium signaling, the ER stress response, and ubiquitin. Remarkably, rapamycin treatment also reversed the social behavior deficits, thus providing a promising potential therapy for TSC-associated ASD.
Advisors/Committee Members: Michael J. Gambello, M.D., PhD., Pramod Dash, Ph.D., Raymond J. Grill, Ph.D..
Subjects/Keywords: Purkinje cell; Tuberous sclerosis; rapamycin; mouse; Tsc2; autism; social; cell death; ER stress; oxidative stress; Medicine and Health Sciences
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APA (6th Edition):
Reith, R. M. (2012). CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/266
Chicago Manual of Style (16th Edition):
Reith, Rachel Michelle. “CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM.” 2012. Doctoral Dissertation, Texas Medical Center. Accessed January 15, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/266.
MLA Handbook (7th Edition):
Reith, Rachel Michelle. “CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM.” 2012. Web. 15 Jan 2021.
Vancouver:
Reith RM. CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM. [Internet] [Doctoral dissertation]. Texas Medical Center; 2012. [cited 2021 Jan 15].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/266.
Council of Science Editors:
Reith RM. CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM. [Doctoral Dissertation]. Texas Medical Center; 2012. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/266
Freie Universität Berlin
27.
Vogt, Lars Bruno.
Evaluation of new CT- and MR-imaging criteria for risk stratification in
patients with tuberous sclerosis complex.
Degree: 2018, Freie Universität Berlin
URL: http://dx.doi.org/10.17169/refubium-9653
► Introduction: Tuberous sclerosis complex (TSC) is a rare hamartomatous disease caused by mutations in the TSC1- or TSC2-gene. Highly variable and often unspecific clinical presentation…
(more)
▼ Introduction:
Tuberous sclerosis complex (TSC) is a rare hamartomatous disease
caused by mutations in the TSC1- or TSC2-gene. Highly variable and often
unspecific clinical presentation can make diagnosis difficult. Late diagnosis
increases the risk of potentially life-threatening complications. For an early
prevention, additional independent diagnosis criteria are required. As a novel
criterion a CT-imaging biomarker is under discussion: Sclerotic bone lesions
(SBLs). So far there are no current studies with larger cohorts. The most
relevant life-threatening TSC-complication are renal hemorrhages resulting
from angiomyolipoma (AML). The risk of renal bleeding increases when AML are
>4 cm. Previous studies demonstrated, that everolimus therapy results in a
reduction of AML-size and risk of bleeding. Therefore it´s difficult to assess
therapeutic response when no size reduction can be measured. In such cases
it´s possible to assess relative MRT-signal intensities to demonstrate early
fatty AML-transformation. SNR (signal-to-noise-ratio) and CNR (contrast-to-
noise-ratio) could represent suitable indicators. Materials/Methods: 89 adult
TSC-patients (50 females) were analyzed. CT-imaging of skull (n=23), thorax
(n=30) and abdomen/pelvis (n=32) were compared to age/sex-matched control
groups. Frequency, size and location pattern of SBLs were evaluated. Test
indicators (cutoff values, sensitivity, specificity) of SBL-frequency were
calculated using ROC-curves. In all TSC-patients under Everolimus T2-fatsat-
MRT-sequences were performed before initiation of therapy and after several
time periods (<3 months: n=21; 3-6 months: n=32; 18-24 months: n=28). Signal
(SNR/CNR) and size changes were measured. In addition, a control group of TSC-
patients without therapy (n=19) was built. Results: A total of 3439 SBLs in
TSC-patients was detected (skull 665; thorax 1426; abdomen/pelvis 1348). In
the matched control groups 157 SBLs were found. ROC-analyses generated optimal
cutoff values with high sensitivities and specificities (skull: ≥5 SBLs; 0,78;
1,0 – thorax: ≥4 SBLs; 0,97; 0,97 – abdomen/pelvis: ≥5 SBLs; 0,94; 0,91). The
anatomical distribution of SBLs differed significantly within all CT-regions.
The mean SBL-diameters in all TSC-groups were significantly higher than in the
control groups. Age, sex, genetics and LAM-diagnosis didn´t relevantly
influence SBL-frequency. A total of 114 AML was evaluated. In all Everolimus
groups CNR dropped significantly. Reductions in SNR and AML-size were still
significant but less pronounced. There were no significant changes in the
control group. Conculsion: It is possible to establish a reliable TSC-
diagnosis based on the SBL-frequency. SBLs are as applicable as novel CT-
imaging marker for TSC-patients. Everolimus therapy in TSC-patients results in
early and pronounced fatty AML-transformation. CNR may serve as additional
indicator for therapeutical success in AML.
Advisors/Committee Members: [email protected] (contact), m (gender), N.N. (firstReferee), N.N. (furtherReferee).
Subjects/Keywords: tuberous sclerosis complex; sclerotic bone lesions; computer tomography; angiomyolipoma; magnetic resonance imaging; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
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APA ·
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Manager
APA (6th Edition):
Vogt, L. B. (2018). Evaluation of new CT- and MR-imaging criteria for risk stratification in
patients with tuberous sclerosis complex. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-9653
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Vogt, Lars Bruno. “Evaluation of new CT- and MR-imaging criteria for risk stratification in
patients with tuberous sclerosis complex.” 2018. Thesis, Freie Universität Berlin. Accessed January 15, 2021.
http://dx.doi.org/10.17169/refubium-9653.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Vogt, Lars Bruno. “Evaluation of new CT- and MR-imaging criteria for risk stratification in
patients with tuberous sclerosis complex.” 2018. Web. 15 Jan 2021.
Vancouver:
Vogt LB. Evaluation of new CT- and MR-imaging criteria for risk stratification in
patients with tuberous sclerosis complex. [Internet] [Thesis]. Freie Universität Berlin; 2018. [cited 2021 Jan 15].
Available from: http://dx.doi.org/10.17169/refubium-9653.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Vogt LB. Evaluation of new CT- and MR-imaging criteria for risk stratification in
patients with tuberous sclerosis complex. [Thesis]. Freie Universität Berlin; 2018. Available from: http://dx.doi.org/10.17169/refubium-9653
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
28.
Hien, Annie.
Regulation of Translation and Synaptic Plasticity by TSC2.
Degree: PhD, Program in Molecular Medicine, 2020, U of Massachusetts : Med
URL: https://escholarship.umassmed.edu/gsbs_diss/1097
► Mutations in TSC2 cause the disorder tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required…
(more)
▼ Mutations in
TSC2 cause the disorder
tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD), but the identity of mRNAs responsive to mGluR-LTD signaling in the normal and TSC brain is largely unknown. We generated
Tsc2+/- mice to model TSC autism and performed ribosome profiling to identify differentially expressed genes following mGluR-LTD in the normal and
Tsc2+/- hippocampus. Ribosome profiling reveals that in <em>Tsc2
+/-</em>mice, RNA-binding targets of Fragile X Mental Retardation Protein (FMRP) are increased. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD signaling failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in
Tsc2+/- mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in the
Tsc2+/- brain. These results suggest a molecular basis for bidirectional regulation of synaptic plasticity by TSC2 and FMRP. Furthermore, deficient mGluR-regulated translation elongation contributes to impaired synaptic plasticity in <em>Tsc2
+/-</em> mice.
Advisors/Committee Members: Joel Richter.
Subjects/Keywords: tuberous sclerosis; fragile X syndrome; autism spectrum disorder; synaptic plasticity; ribosome profiling; Molecular and Cellular Neuroscience
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APA (6th Edition):
Hien, A. (2020). Regulation of Translation and Synaptic Plasticity by TSC2. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/1097
Chicago Manual of Style (16th Edition):
Hien, Annie. “Regulation of Translation and Synaptic Plasticity by TSC2.” 2020. Doctoral Dissertation, U of Massachusetts : Med. Accessed January 15, 2021.
https://escholarship.umassmed.edu/gsbs_diss/1097.
MLA Handbook (7th Edition):
Hien, Annie. “Regulation of Translation and Synaptic Plasticity by TSC2.” 2020. Web. 15 Jan 2021.
Vancouver:
Hien A. Regulation of Translation and Synaptic Plasticity by TSC2. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2020. [cited 2021 Jan 15].
Available from: https://escholarship.umassmed.edu/gsbs_diss/1097.
Council of Science Editors:
Hien A. Regulation of Translation and Synaptic Plasticity by TSC2. [Doctoral Dissertation]. U of Massachusetts : Med; 2020. Available from: https://escholarship.umassmed.edu/gsbs_diss/1097
IUPUI
29.
Dock, Murray.
Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlations.
Degree: 2000, IUPUI
URL: http://hdl.handle.net/1805/4353
► Indiana University-Purdue University Indianapolis (IUPUI)
The purpose of this investigation was to study the incidence of enamel pitting and gingival fibromas in patients with tuberous…
(more)
▼ Indiana University-Purdue University Indianapolis (IUPUI)
The purpose of this investigation was to study the incidence of enamel pitting and gingival fibromas in patients with tuberous sclerosis complex (TSC) and relate these findings to other physical findings of TSC, to sporadic and familial disease, and to specific TSC2 mutations. Methods: A total of 104 patients between 1 and 51 years of age were examined for enamel pits and gingival fibromas. All study subjects had a definitive diagnosis of TSC and were participants in a related study that provided results from MRI scans of the brain, echocardiography, renal ultrasound, neuropsychological assessments, and retinal examinations. Blood samples were obtained from each participant for DNA extraction and subsequent TSC mutational analysis. Results: Enamel pitting was seen in 29% of patients between 1 and 6 years of age, in 90% between 6 and 13 years of age, and in 100% of patients in the permanent 113 dentition. The majority of the pits were pinpoint sized and primarily affected the maxillary anterior arch. The maxillary central incisor was the most often affected permanent tooth and the maxillary canine was the most often affected primary tooth. Gingival fibromas were apparent in 47% of subjects in the mixed dentition and in 70% of subjects in the permanent dentition. Only one patient out of 31 in the primary dentition had a gingival fibroma. The majority of fibromas affected the interdental papilla of the maxillary anterior arch. There were few significant findings relating the degree and/or severity of enamel pitting and/or gingival fibromas to other physical findings of TSC. Enamel pitting in primary as well as permanent teeth were found to be strongly related to the presence of facial angiofibromas and a somewhat weaker association was seen with cardiac arrhythmias. Gingival fibromas were strongly related to the presence of facial angiofibromas and more weakly related to retinal lesions. There were no distinctions
apparent between oral findings in sporadic and familial TSC nor were there any genotype-phenotype correlations between oral findings and TSC2 mutations. Conclusion: The combination of enamel pitting and gingival fibromas, as minor
features of TSC, should raise the suspicion level regarding tuberous sclerosis as a
diagnosis. Both are important minor features frequently seen which may help in
establishing a definitive diagnosis. Scanning the dentition and gingiva is noninvasive, is
inexpensive, and should be included in evaluating all patients suspect of a diagnosis of
tuberous sclerosis.
Advisors/Committee Members: Dean, Jeffrey A., Sanders, Brian J., Zunt, Susan L., 1951-, Franz, David N., Schorry, Elizabeth K., Avery, David R..
Subjects/Keywords: Tuberous sclerosis; Dental Enamel – abnormalities; Gingiva; Fibroma
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APA ·
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Export
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APA (6th Edition):
Dock, M. (2000). Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlations. (Thesis). IUPUI. Retrieved from http://hdl.handle.net/1805/4353
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Dock, Murray. “Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlations.” 2000. Thesis, IUPUI. Accessed January 15, 2021.
http://hdl.handle.net/1805/4353.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Dock, Murray. “Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlations.” 2000. Web. 15 Jan 2021.
Vancouver:
Dock M. Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlations. [Internet] [Thesis]. IUPUI; 2000. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1805/4353.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Dock M. Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlations. [Thesis]. IUPUI; 2000. Available from: http://hdl.handle.net/1805/4353
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
30.
Verhoef, S.
Clinical and Molecular Genetics of Tuberous Sclerosis Complex.
Degree: 2001, Erasmus University Medical Center
URL: http://hdl.handle.net/1765/12098
Subjects/Keywords: TSC; clinical genetics; klinische genetica; tuberous sclerosis complex
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Verhoef, S. (2001). Clinical and Molecular Genetics of Tuberous Sclerosis Complex. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/12098
Chicago Manual of Style (16th Edition):
Verhoef, S. “Clinical and Molecular Genetics of Tuberous Sclerosis Complex.” 2001. Doctoral Dissertation, Erasmus University Medical Center. Accessed January 15, 2021.
http://hdl.handle.net/1765/12098.
MLA Handbook (7th Edition):
Verhoef, S. “Clinical and Molecular Genetics of Tuberous Sclerosis Complex.” 2001. Web. 15 Jan 2021.
Vancouver:
Verhoef S. Clinical and Molecular Genetics of Tuberous Sclerosis Complex. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 2001. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1765/12098.
Council of Science Editors:
Verhoef S. Clinical and Molecular Genetics of Tuberous Sclerosis Complex. [Doctoral Dissertation]. Erasmus University Medical Center; 2001. Available from: http://hdl.handle.net/1765/12098
◁ [1] [2] [3] ▶
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Open Access Theses and Dissertations
