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Vanderbilt University
1.
Shen, Dingding.
Characterization of GABAA receptor subunit mutations associated with epileptic encephalopathies.
Degree: PhD, Neuroscience, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/14271 
► Epileptic encephalopathies (EEs) are a devastating group of severe childhood onset epilepsies with medication resistant seizures and poor developmental outcomes. Many EEs have a genetic…
(more)
▼ Epileptic encephalopathies (EEs) are a devastating group of severe childhood onset epilepsies with medication resistant seizures and poor developmental outcomes. Many EEs have a genetic etiology and are often associated with de novo mutations in genes coding for proteins involved in synaptic transmission, including GABAA receptor subunit genes. A better understanding of GABAA receptor subunit mutations associated with EEs in vitro and in vivo will facilitate epilepsy diagnosis as well as treatments in the future. Here we employed a combination of next generation sequencing and in vitro functional assays and established for the first time that missense GABRG2 mutations are genetic risk factors for EEs. In addition, we focused on three nonsense GABRG2 mutations associated with epilepsies of different severities and demonstrated that they resulted in different structural disturbance and different suppression of wild-type partnering subunits. Finally we investigated the performance of heterozygous knock-in (KI) mice which bear the GABRB3(N110D) mutation associated with infantile spasms (Gabrb3+/N110D KI mice) in a battery of behavioral tasks, showing that they had significantly abnormal neurobehavioral profiles persisting into adulthood. To conclude, we have shown meaningful functional and structural changes for EE-associated GABRG2 mutations in vitro, and have determined the behavioral comorbidities of KI mice harboring a human infantile spasms GABRB3 mutation in vivo.
Advisors/Committee Members: Kevin C. Ess (committee member), Robert L. Macdonald (committee member), Martin J. Gallagher (committee member), Douglas G. McMahon (Committee Chair).
Subjects/Keywords: Epileptic encephalopathies; GABAA receptor
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APA (6th Edition):
Shen, D. (2017). Characterization of GABAA receptor subunit mutations associated with epileptic encephalopathies. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14271
Chicago Manual of Style (16th Edition):
Shen, Dingding. “Characterization of GABAA receptor subunit mutations associated with epileptic encephalopathies.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/14271.
MLA Handbook (7th Edition):
Shen, Dingding. “Characterization of GABAA receptor subunit mutations associated with epileptic encephalopathies.” 2017. Web. 20 Jan 2021.
Vancouver:
Shen D. Characterization of GABAA receptor subunit mutations associated with epileptic encephalopathies. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/14271.
Council of Science Editors:
Shen D. Characterization of GABAA receptor subunit mutations associated with epileptic encephalopathies. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/14271
Vanderbilt University
2.
West, Kathryn Louise.
Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains.
Degree: PhD, Biomedical Engineering, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/14525
► Advanced neuroimaging techniques provide the possibility to non-invasively understand and monitor white matter during development and disease. While data from quantitative MRI techniques, such as…
(more)
▼ Advanced neuroimaging techniques provide the possibility to non-invasively understand and monitor white matter during development and disease. While data from quantitative MRI techniques, such as multiexponential T2 (MET2) and quantitative magnetization transfer (qMT), correlate with myelin content, neither provide an absolute measure of the myelin volume fraction (MVF). Additionally, in preclinical studies, despite time-intensity and small tissue samples, histology remains the gold standard for quantitatively assessing changes in myelin content and white matter microstructural properties, such as myelin thickness and the g-ratio (ratio of axon radius to myelinated fiber radius). Therefore, the work in this dissertation first established and validated methods for MVF imaging from MET2 and qMT against quantitative electron microscopy. We show strong agreement in adult, control mice along with three mouse models of white matter disease. Next, we applied MVF imaging in mice during normal development and observe good agreement between MET2 and qMT and with expected myelin development. To further investigate specific changes in myelin microstructure, recent methods proposed measuring the g-ratio from MRI (gMRI). We revised the model and displayed with quantitative histology that gMRI provides an axon-area-weighted g-ratio. Calculating gMRI requires an accurate measure of MVF; thus, we utilize our MVF imaging techniques to measure gMRI in mouse brain and detect changes in g-ratio with disease in agreement with quantitative histology. In short, we develop and validate measures of MVF and g-ratio from MRI which have the potential to non-invasively provide more specific and thorough assessment of white matter not obtainable with currently used methods.
Advisors/Committee Members: Adam W. Anderson (committee member), Kevin C. Ess (committee member), Daniel F. Gochberg (committee member), John C. Gore (committee member), Mark D. Does (Committee Chair).
Subjects/Keywords: magnetization transfer; multiexponential T2; myelin; MRI; neuroimaging; histology; g-ratio
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APA (6th Edition):
West, K. L. (2016). Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14525
Chicago Manual of Style (16th Edition):
West, Kathryn Louise. “Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/14525.
MLA Handbook (7th Edition):
West, Kathryn Louise. “Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains.” 2016. Web. 20 Jan 2021.
Vancouver:
West KL. Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/14525.
Council of Science Editors:
West KL. Development and Evaluation of Relaxation-Based Measures of Myelin Content and Microstructure in Rodent Brains. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/14525
Vanderbilt University
3.
Huang, Xuan.
Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14755
► Epilepsy is a neurological disorder affecting almost one percent of the population, and genetic epilepsy are those caused by a presumed or unknown genetic factor(s).…
(more)
▼ Epilepsy is a neurological disorder affecting almost one percent of the population, and genetic epilepsy are those caused by a presumed or unknown genetic factor(s). Mutations in GABAA receptors, pentameric chloride ion channels mediating fast inhibitory neurotransmission, have been identified in patients and families with epilepsy and found to cause epilepsy in animal models. The majority of synaptic GABAARs are αβγ type receptors composed of two α, two β and one γ2 subunits, and half of these epilepsy-associated GABAAR mutations are located in γ2 subunits encoded by the GABRG2 gene. A better understanding of how different types of epilepsy-associated GABRG2 mutations affect receptor trafficking and channel function, and how these mutations cause epilepsy in mouse models, will facilitate future epilepsy diagnosis as well as treatments. Here we have studied three different types of mutations represented by GABRG2(N79S, R82Q, and P83S), GABRG2(Q40X), and GABRG2(Q390X), in cultured HEK cells or animal models. We found that missense mutations located in receptor interface will disrupt receptor assembly and trafficking, which may be improved by slowing receptor biogenesis. We found that nonsense mutations showing loss of function could be partially rescued using gentamicin-induced stop codon read-through. Finally we showed that gene-target therapy could reverse the seizure phenotype in a mouse model carrying a detrimental mutation with dominant negative effects. To conclude, we have shown different molecular mechanisms are associated with these mutations, and distinct mutation-specific therapy may be potentially developed for future treatments.
Advisors/Committee Members: Richard M. Breyer (committee member), Kevin C. Ess (committee member), Robert L. Macdonald (committee member), Alfred L. George (Committee Chair), Bruce D. Carter (Committee Chair).
Subjects/Keywords: GABA(A) receptors; GABRG2; genetic epilepsy; mutation; therapy
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APA (6th Edition):
Huang, X. (2014). Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14755
Chicago Manual of Style (16th Edition):
Huang, Xuan. “Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/14755.
MLA Handbook (7th Edition):
Huang, Xuan. “Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities.” 2014. Web. 20 Jan 2021.
Vancouver:
Huang X. Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/14755.
Council of Science Editors:
Huang X. Epilepsy-associated mutations in GABRG2: characterization and therapeutic opportunities. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14755
Vanderbilt University
4.
Jorge, Benjamin S.
Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14387
► Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are…
(more)
▼ Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are genetic in origin. Variable expressivity is commonly observed in families with inherited mutations in epilepsy-associated genes, suggesting that variation in genetic modifiers may contribute to epilepsy phenotypes. We previously identified the modulatory voltage-gated potassium channel subunit, Kcnv2, as a candidate modifier gene in a transgenic mouse model of epilepsy. This dissertation outlines: the validation of Kcnv2 as a quantitative modifier of epilepsy in mice; the identification of KCNV2 variants in pediatric epilepsy patients; the determination of Kcnv2 regulatory regions; and the identification of mutations in a delayed-rectifier potassium channel gene, KCNB1, in individuals with epileptic encephalopathy. These studies highlight the importance of delayed-rectifier potassium current in governing neuronal excitability and demonstrate the utility of identifying and characterizing genetic modifiers to elucidate mechanisms of pathogenesis.
Advisors/Committee Members: Kevin C. Ess, M.D., Ph.D. (committee member), Jennifer A. Kearney, Ph.D. (committee member), Douglas P. Mortlock, Ph.D. (committee member), Alfred L. George, Jr., M.D. (Committee Chair).
Subjects/Keywords: potassium channel; epileptic encephalopathy; mouse model; genetics; whole-exome sequencing; epilepsy
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APA (6th Edition):
Jorge, B. S. (2014). Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14387
Chicago Manual of Style (16th Edition):
Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/14387.
MLA Handbook (7th Edition):
Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Web. 20 Jan 2021.
Vancouver:
Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/14387.
Council of Science Editors:
Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14387
Vanderbilt University
5.
Tidball, Andrew Martin.
A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14230
► The essential micronutrient manganese is enriched in brain, especially the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels,…
(more)
▼ The essential micronutrient manganese is enriched in brain, especially the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested manganese alterations occur in Huntington’s disease (HD). We found that p53 phosphorylation is highly responsive to manganese levels in human and mouse striatal-like neuroprogenitors. The Ataxia Telangiectasia Mutated (ATM) kinase is responsible for this manganese-dependent phosphorylation of p53. Activation of ATM-p53 by manganese was severely blunted by pathogenic alleles of Huntingtin. HD neuroprogenitors exhibited a highly manganese selective deficit in ATM kinase activation, since DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. Manganese was previously shown to activate ATM kinase in cell-free assays. We found that human HD neuroprogenitors have reduced intracellular manganese with neurologically relevant manganese exposures. Pharmacological manipulation to equalize manganese between HD and control neuroprogenitors rescued the ATM-p53 signaling deficit. The compound that normalized these levels was the small molecule, KB-R7943, a known inhibitor sodium/calcium exchanger (NCX) inhibitor. However, the mechanism by which KB-R7943 corrects manganese accumulation does not seem to be via direct inhibition of the NCX transporters. We also demonstrated a severe deficit in NCX1 expression in HD cells that may also play a key role in the HD manganese deficiency.
Huntington’s disease cells also show increased genomic instability and DNA damage signaling under basal conditions. Manganese is known to be an important cofactor for several enzymes involved in DNA repair and replication, and we found that the manganese deficiency was most severe in the nucleus compared with other compartments. Manganese supplementation reduced the elevated DNA damage signaling to those found in non-HD cells suggesting that manganese deficiency underlies this phenotype
In short, the ATM-p53 signaling pathway is a manganese responsive signaling pathway. Manganese is an important cofactor with diminished accumulation in HD cell models. These reduced levels may be the reason for observed increases in DNA damage and genomic instability. Further experimentation is needed to elucidate the mechanism of manganese accumulation deficiency mechanism in HD and the KB-R7943 rescue.
Advisors/Committee Members: Christopher V. Wright (committee member), Michael Aschner (committee member), Aaron B. Bowman (committee member), Kevin C. Ess (Committee Chair).
Subjects/Keywords: manganese; induced-pluripotent stem cells; ATM; p53; cell signaling; cytotoxicity; genomic instability; Huntingtons disease
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APA (6th Edition):
Tidball, A. M. (2014). A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14230
Chicago Manual of Style (16th Edition):
Tidball, Andrew Martin. “A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/14230.
MLA Handbook (7th Edition):
Tidball, Andrew Martin. “A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling.” 2014. Web. 20 Jan 2021.
Vancouver:
Tidball AM. A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/14230.
Council of Science Editors:
Tidball AM. A Manganese-Handling Deficit in Huntington’s Disease Selectively Impairs ATM-p53 Signaling. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14230
Vanderbilt University
6.
Kumar, Kevin Krishan.
Investigation of Neuronal Manganese Regulation in Physiology and Disease Using High Throughput Screening, Induced Pluripotent Stem Cells, and Chemical Biology Approaches.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14021
► Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of…
(more)
▼ Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of neurodegenerative disorders, such as parkinsonism and Huntington’s disease (HD). However, beyond several non-selective transporters, little is known about the intracellular processes regulating neuronal Mn homeostasis. We hypothesized that small molecules that modulate intracellular Mn could provide insight into cell-level Mn regulatory mechanisms. We performed a high throughput screen of 40,167 small molecules for modifiers of cellular Mn content. Utilizing the identified small molecules, we tested for differential regulation of Mn handling in human floor-plate lineage dopaminergic neurons, a lineage especially vulnerable to environmental Mn exposure. We report differential Mn accumulation between developmental stages and stage-specific differences in the Mn-altering activity of individual small molecules, demonstrating cell-level regulation of Mn content across neuronal differentiation. In a parallel study, we sought to reveal any cellular metabolic phenotypes influenced by Mn exposure and/or the mutant HD genotype using an unbiased metabolomics approach. Our analysis revealed metabolic evidence of an interaction between the HD genotype and environmentally relevant Mn exposures in a striatal neural lineage. The metabolic phenotypes detected support existing hypotheses that changes in energetic processes underlie the pathogenesis of both HD and Mn neurotoxicity.
Advisors/Committee Members: Aaron B. Bowman (committee member), Joseph S. Neimat (committee member), Michael Aschner (committee member), C. David Weaver (committee member), Daniel O. Claassen (committee member), Kevin C. Ess (Committee Chair).
Subjects/Keywords: High Throughput Screening; Manganese; Neurodegenerative diseases; Human Induced Pluripotent Stem Cells; Metabolomics
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APA (6th Edition):
Kumar, K. K. (2014). Investigation of Neuronal Manganese Regulation in Physiology and Disease Using High Throughput Screening, Induced Pluripotent Stem Cells, and Chemical Biology Approaches. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14021
Chicago Manual of Style (16th Edition):
Kumar, Kevin Krishan. “Investigation of Neuronal Manganese Regulation in Physiology and Disease Using High Throughput Screening, Induced Pluripotent Stem Cells, and Chemical Biology Approaches.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/14021.
MLA Handbook (7th Edition):
Kumar, Kevin Krishan. “Investigation of Neuronal Manganese Regulation in Physiology and Disease Using High Throughput Screening, Induced Pluripotent Stem Cells, and Chemical Biology Approaches.” 2014. Web. 20 Jan 2021.
Vancouver:
Kumar KK. Investigation of Neuronal Manganese Regulation in Physiology and Disease Using High Throughput Screening, Induced Pluripotent Stem Cells, and Chemical Biology Approaches. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/14021.
Council of Science Editors:
Kumar KK. Investigation of Neuronal Manganese Regulation in Physiology and Disease Using High Throughput Screening, Induced Pluripotent Stem Cells, and Chemical Biology Approaches. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14021
Vanderbilt University
7.
Bruntz, Ronald Chase.
Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.
Degree: PhD, Pharmacology, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/10427
► The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to…
(more)
▼ The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to generate a choline headgroup and the important lipid second messenger, phosphatidic acid (PtdOH). PLD family members are found in a diverse range of species from viruses to humans and regulate many important physiological processes including cytoskeletal rearrangements, cell migration, immune response, and cell proliferation. As such, PLD promotes oncogenic processes and elevated PLD activity has been documented in many types of cancerous tissue and derived cell lines. PLD activity is associated with cell cycle progression, resistance to apoptotic stimuli, and tumor cell invasion, but the molecular mechanisms of these PLD-mediated processes are largely uncharacterized. The goal of this project was to identify and characterize novel PLD-protein complexes in order to further understand the mechanisms by which PLD promotes cancer growth and survival. In this dissertation, PLD-derived PtdOH is demonstrated to be a novel regulator of pro-survival Akt kinase in glioblastoma cells by regulating membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. Additionally, PLD is shown to interact with a number of metabolic enzymes and a potential role for the regulation of cellular bioenergetics in GBM is explored. The results of this research provide mechanistic insight into PLD-mediated cancer cell survival.
Advisors/Committee Members: Brian E. Wadzinski (committee member), Daniel C. Liebler (committee member), H. Alex Brown (committee member), Heidi E. Hamm (committee member), Kevin C. Ess (committee member), John H. Exton (Committee Chair).
Subjects/Keywords: phospholipase D; phosphatidic acid; cancer; Akt; cell signaling; autophagy
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APA (6th Edition):
Bruntz, R. C. (2014). Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10427
Chicago Manual of Style (16th Edition):
Bruntz, Ronald Chase. “Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 20, 2021.
http://hdl.handle.net/1803/10427.
MLA Handbook (7th Edition):
Bruntz, Ronald Chase. “Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.” 2014. Web. 20 Jan 2021.
Vancouver:
Bruntz RC. Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 20].
Available from: http://hdl.handle.net/1803/10427.
Council of Science Editors:
Bruntz RC. Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/10427
Vanderbilt University
8.
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 20, 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. 20 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 20].
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
. 
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