+publisher:"Cornell University" +contributor:("Kurpios, Natasza")

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Cornell University

1. Farrar, Emily. Initiating Mechanisms Of Aortic Valve Disease: A Role For The Endothelium.

Degree: PhD, Biomedical Engineering, 2015, Cornell University

URL: http://hdl.handle.net/1813/41087

► The objective of this thesis was to unveil initiating mechanisms of aortic valve disease, a serious and prevalent cardiovascular pathology affecting 2.8% of Americans over… (more)

▼ The objective of this thesis was to unveil initiating mechanisms of aortic valve disease, a serious and prevalent cardiovascular pathology affecting 2.8% of Americans over the age of 75. Currently, valve disease has no known causes and no existing treatments except for cardiothoracic surgery. Identification of initiating mechanisms will lead to new diagnostic markers and treatment strategies that would allow for early intervention and eventually the prevention of valve disease. This work primarily focuses on the influence of the inflammatory cytokine tumor necrosis factor-[alpha] (TNF[alpha]) on the endothelial cells that line the aortic valve. By focusing on inflammation and the endothelium, both "first responders" to disease conditions in the valve environment, we hoped to unveil new mechanisms that could govern early stages of the disease. In this thesis, we have demonstrated that TNF[alpha] causes adult valve endothelial cells to produce destructive free radicals, dysregulating the delicate oxidate stress state of the valve. TNF[alpha] also drives endothelial cells to become mesenchymal via NF[kappa]B signaling, a reactivation of an embryonic pathway important to shaping the valve leaflets in utero. We further found that NF[kappa]B signaling drives endothelial participation in the later stages of valve calcification, showing in vivo that NF[kappa]B is a critical mediator of valve dysfunction. We have also demonstrated a role for the stem cell transcription factor Oct4 in governing how valve endothelial cells change phenotype throughout disease. These findings have led to improved understanding of how NF[kappa]B and Oct4 govern interstitial cell calcification, in the later stages of valve disease. Finally, we have used the biomechanical engineering strengths of our lab to investigate how the regulation of valve interstitial cell contractility is crucial to progression of calcification in the valve. My hope is that the results presented in this thesis will create a basic science foundation for the development of diagnostics and therapies to help patients suffering from aortic valve disease, especially those ineligible for surgical amelioration. Our in vitro and in vivo findings regarding the role of inflammation in endothelial dysfunction provide new evidence for the design of drugs targeting the NF[kappa]B pathway for aortic valve disease. Advisors/Committee Members: Butcher,Jonathan T. (chair), King,Cynthia A. (committee member), Kurpios,Natasza (committee member).

Subjects/Keywords: Inflammation; calcification; NF-kappa B

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APA (6^th Edition):

Farrar, E. (2015). Initiating Mechanisms Of Aortic Valve Disease: A Role For The Endothelium. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/41087

Chicago Manual of Style (16^th Edition):

Farrar, Emily. “Initiating Mechanisms Of Aortic Valve Disease: A Role For The Endothelium.” 2015. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/41087.

MLA Handbook (7^th Edition):

Farrar, Emily. “Initiating Mechanisms Of Aortic Valve Disease: A Role For The Endothelium.” 2015. Web. 06 Mar 2021.

Vancouver:

Farrar E. Initiating Mechanisms Of Aortic Valve Disease: A Role For The Endothelium. [Internet] [Doctoral dissertation]. Cornell University; 2015. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/41087.

Council of Science Editors:

Farrar E. Initiating Mechanisms Of Aortic Valve Disease: A Role For The Endothelium. [Doctoral Dissertation]. Cornell University; 2015. Available from: http://hdl.handle.net/1813/41087

2. Druso, Joseph Edward. IDENTIFYING AND ANALYZING THE ROLES OF CDC42 DURING MAMMARY GLAND DEVELOPMENT AND TRANSFORMATION.

Degree: PhD, Pharmacology, 2017, Cornell University

URL: http://hdl.handle.net/1813/47715

► The small GTPase Cdc42 is an essential signaling molecule in multiple cellular processes, including proliferation, migration, division and apoptosis. The overexpression of Cdc42 is found… (more)

▼ The small GTPase Cdc42 is an essential signaling molecule in multiple cellular processes, including proliferation, migration, division and apoptosis. The overexpression of Cdc42 is found in certain breast carcinomas, bringing to question its roles in normal mammary cell function and during breast cancer progression. In this thesis, I have examined the roles of Cdc42 during mammary gland development, and then analyzed the effects of overactive Cdc42 signaling on mammary epithelial cells (MECs). To accomplish this, I used an in vivo mouse model as well as primary cell culture systems. In the initial study, the conditional-knockout of Cdc42 in the epithelia of adult mouse mammary glands resulted in the altered cellular localization of Par complex members, as well as E-cadherin. These changes accompanied a disorganization of the epithelial cells within the mammary gland, and led to insufficient lactation. This loss-of-function mouse model showed that Cdc42 is essential for the proper maintenance of both apical-basal cell polarity and E-cadherin-based cell-cell junctions in the adult mammary gland. These results raised further interest concerning the roles Cdc42 may have in breast carcinoma development, in which proper apical-basal cell polarity and cell-cell communication are commonly lost. I next examined the effects of aberrant Cdc42 signaling in primary MECs by utilizing the constitutively-active Cdc42[F28L] mutant. In a monolayer culture system, Cdc42[F28L] stimulated the formation of actin-based stress fibers, and gave rise to multi-nucleated cells, while in a three-dimensional model system it drove the primary MECs toward an invasive phenotype in an IQGAP1-dependent manner. The primary MECs expressing Cdc42[F28L] lost the proper localization of E-cadherin at cell-cell contacts and no longer formed normal, hollowed alveolar lumens, but instead began to abnormally fill the luminal space and invade out into the surrounding environment. A common phenotype exhibited by these model systems was the proper maintenance of E-cadherin-based cell-cell contacts between mammary epithelial cells. Interestingly, both the deletion of Cdc42 and its constitutive activation resulted in abnormal E-cadherin expression and localization within mammary epithelial cells. IQGAP1 is likely the primary Cdc42 effector responsible for these phenotypes, as it can both regulate E-cadherin stability at cell-cell junctions as well as bundle microtubules at the leading edge of invasive cells. These studies suggest IQGAP1 is a critical signaling effector of Cdc42 in adult mammary epithelial cells and that, when not properly regulated, it can shift the epithelia toward an invasive phenotype. Advisors/Committee Members: Cerione, Richard A (chair), Linder, Maurine E. (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: Breast cancer; Cdc42; Lactation; Mammary gland; Transformation; Cellular biology; Developmental biology

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APA (6^th Edition):

Druso, J. E. (2017). IDENTIFYING AND ANALYZING THE ROLES OF CDC42 DURING MAMMARY GLAND DEVELOPMENT AND TRANSFORMATION. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/47715

Chicago Manual of Style (16^th Edition):

Druso, Joseph Edward. “IDENTIFYING AND ANALYZING THE ROLES OF CDC42 DURING MAMMARY GLAND DEVELOPMENT AND TRANSFORMATION.” 2017. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/47715.

MLA Handbook (7^th Edition):

Druso, Joseph Edward. “IDENTIFYING AND ANALYZING THE ROLES OF CDC42 DURING MAMMARY GLAND DEVELOPMENT AND TRANSFORMATION.” 2017. Web. 06 Mar 2021.

Vancouver:

Druso JE. IDENTIFYING AND ANALYZING THE ROLES OF CDC42 DURING MAMMARY GLAND DEVELOPMENT AND TRANSFORMATION. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/47715.

Council of Science Editors:

Druso JE. IDENTIFYING AND ANALYZING THE ROLES OF CDC42 DURING MAMMARY GLAND DEVELOPMENT AND TRANSFORMATION. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/47715

Cornell University

3. Diamantides, Nicole. DEVELOPMENT OF COLLAGEN BIOINKS FOR CARTILAGE BIOPRINTING.

Degree: PhD, Biomedical Engineering, 2019, Cornell University

URL: http://hdl.handle.net/1813/70023

► Bioprinting, or the use of three-dimensional printing technology to produce scaffolds and cellularized tissue constructs, is becoming more prominent in the tissue engineering and regenerative… (more)

▼ Bioprinting, or the use of three-dimensional printing technology to produce scaffolds and cellularized tissue constructs, is becoming more prominent in the tissue engineering and regenerative medicine fields. However, a major limiting factor to the field remains the development of adequate bioinks. Bioinks must be printable, cell-friendly, and exhibit mechanical properties necessary for construct implantation. Collagen bioinks are promising due to their cell-friendly properties but exhibit weak mechanical properties and slow gelation that present challenges for bioprinting applications. The overall goal of this study is to develop improved collagen bioinks for cartilage bioprinting that exhibit improved mechanics and printability while maintaining cell-friendliness. There are many parameters that can be used to tune the properties of collagen hydrogels, such as collagen concentration, gelation temperature, pepsin treatment, pH, enzymatic crosslinking, photocrosslinking by light activated riboflavin, and non-enzymatic glycation. Despite all this knowledge, except for collagen concentration, none of these parameters have been applied to the development of collagen bioink formulations. Additionally, bioinks are intended to contain encapsulated cells, however, it is not understood how the incorporation of cells could affect the performance of collagen bioinks. This work begins to investigate these collagen-tuning parameters to develop improved collagen bioinks that exhibit high shape fidelity, printability, and cell-friendliness. This was achieved by first determining which rheological properties are best able to predict collagen bioink printability by correlating the rheological properties and printability of collagen bioinks with blue light activated riboflavin crosslinking and pH variations (Chapter 2). The ability to print with cells and for those cells to survive and thrive is a major necessity of bioprinting. Therefore, the effect of the incorporation of cells on collagen bioink rheology and printability and how the printing process affects cell viability was determined (Chapter 3). Lastly, to improve collagen mechanics in a more cell-friendly manner, the effects of crosslinking through non-enzymatic glycation of collagen was investigated (Chapter 4). Advisors/Committee Members: Bonassar, Lawrence (chair), Kurpios, Natasza (committee member), Butcher, Jonathan T. (committee member).

Subjects/Keywords: 3D bioprinting; cartilage; collagen; printability; rheology; tissue engineering

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APA (6^th Edition):

Diamantides, N. (2019). DEVELOPMENT OF COLLAGEN BIOINKS FOR CARTILAGE BIOPRINTING. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/70023

Chicago Manual of Style (16^th Edition):

Diamantides, Nicole. “DEVELOPMENT OF COLLAGEN BIOINKS FOR CARTILAGE BIOPRINTING.” 2019. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/70023.

MLA Handbook (7^th Edition):

Diamantides, Nicole. “DEVELOPMENT OF COLLAGEN BIOINKS FOR CARTILAGE BIOPRINTING.” 2019. Web. 06 Mar 2021.

Vancouver:

Diamantides N. DEVELOPMENT OF COLLAGEN BIOINKS FOR CARTILAGE BIOPRINTING. [Internet] [Doctoral dissertation]. Cornell University; 2019. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/70023.

Council of Science Editors:

Diamantides N. DEVELOPMENT OF COLLAGEN BIOINKS FOR CARTILAGE BIOPRINTING. [Doctoral Dissertation]. Cornell University; 2019. Available from: http://hdl.handle.net/1813/70023

Cornell University

4. Choo, Ezen. MATERNAL TASTE FUNCTION AND THE PROGRAMMING OF UNHEALTHY TASTE RESPONSES IN OFFSPRING.

Degree: PhD, Pharmacology, 2017, Cornell University

URL: http://hdl.handle.net/1813/56950

► Despite the importance of the maternal diet to supply adequate nutrition to the developing fetus, little is known about how the maternal taste system changes… (more)

▼ Despite the importance of the maternal diet to supply adequate nutrition to the developing fetus, little is known about how the maternal taste system changes during pregnancy; and further if maternal over-nutrition has any long-term impact on the taste system of the offspring in adulthood. Given that more than half of women at childbearing age are considered to be overweight or obese, it is vital to understand how taste can change during pregnancy, and further, to study offspring taste development in the context of maternal obesity. The following experiments were designed to investigate the taste system at the level of behavior, morphology, and gene expression in pregnant mice. In brief-access taste testing with partially food and water restricted mice, licking responses to sucrose decreased during pregnancy and returned to baseline postpartum. Taste bud morphology was unchanged across pregnancy, however taste receptor expression levels were altered across multiple time points during gestation and postpartum. The results indicate that the physiological changes induced by pregnancy can influence taste gene expression, and that interventions focused on the taste bud represent a useful strategy to enhance offspring fitness through maternal intake. The long-term effects of gestational obesity were studied by providing maternal mice with ad libitum high-fat diet throughout pregnancy, weaning their offspring onto normal chow, and studying the taste behavior of the offspring as adults. The adult offspring of mice fed a high fat diet showed enhanced licking responses to sucrose in brief-access testing. Despite only having contact with the high-fat diet in utero and through lactation, this behavior was associated with an increase in sweet receptor expression, and an increase in intake for sweet solutions and the high-fat diet. It is possible that this altered taste system may arise from early fetal programming. In summation, these findings highlight the importance of studying maternal diet and the long-term impacts of maternal obesity on the offspring taste system. Greater understanding of how the maternal diet contributes to the development of the offspring is critical for finding solutions to overcome diseases related to over-nutrition, and to promote healthy eating habits for children who struggle with obesity and diabetes. Advisors/Committee Members: Dando, Robin (chair), Kurpios, Natasza (committee member), Roberson, Mark Stephen (committee member), Linster, Christiane (committee member).

Subjects/Keywords: high fat diet; maternal; Pregnancy; Obesity; offspring; taste; Pharmacology; Neurosciences; physiology

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APA (6^th Edition):

Choo, E. (2017). MATERNAL TASTE FUNCTION AND THE PROGRAMMING OF UNHEALTHY TASTE RESPONSES IN OFFSPRING. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/56950

Chicago Manual of Style (16^th Edition):

Choo, Ezen. “MATERNAL TASTE FUNCTION AND THE PROGRAMMING OF UNHEALTHY TASTE RESPONSES IN OFFSPRING.” 2017. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/56950.

MLA Handbook (7^th Edition):

Choo, Ezen. “MATERNAL TASTE FUNCTION AND THE PROGRAMMING OF UNHEALTHY TASTE RESPONSES IN OFFSPRING.” 2017. Web. 06 Mar 2021.

Vancouver:

Choo E. MATERNAL TASTE FUNCTION AND THE PROGRAMMING OF UNHEALTHY TASTE RESPONSES IN OFFSPRING. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/56950.

Council of Science Editors:

Choo E. MATERNAL TASTE FUNCTION AND THE PROGRAMMING OF UNHEALTHY TASTE RESPONSES IN OFFSPRING. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/56950

Cornell University

5. Chu, Erin Tsi-Jia. MECHANISMS AND CONSEQUENCES OF DNA METHYLATION IN TWO MODEL SPECIES.

Degree: PhD, Comparative Biomedical Sciences, 2017, Cornell University

URL: http://hdl.handle.net/1813/59013

► Epigenetic modifications are known to regulate gene expression in a heritable manner, and can broadly be divided into three interacting classes: DNA methylation, histone modifications,… (more)

▼ Epigenetic modifications are known to regulate gene expression in a heritable manner, and can broadly be divided into three interacting classes: DNA methylation, histone modifications, and chromatin interactions. While the trans acting factors that establish, maintain, and remove DNA methylation are well-known, the cis acting mechanisms that direct DNA methylation to specific genomic locations remain elusive. Two gene classes offer insights into cis-acting mechanisms for DNA methylation: imprinted loci, and transposable elements. A locus spanning both is the murine Rasgrf1 locus. Rasgrf1 has a cis element, a series of tandem repeats, required for DNA methylation, but also harbors a long noncoding RNA, the pitRNA. The pitRNA is driven by the repeats and is targeted by piRNAs, small RNAs that mediate transposable element methylation in the mammalian male germline. However, the effects of the pitRNA versus the repeats have not yet been separated. My work, where I used CRISPR/Cas9 genome editing to generate a targeted mutant system permitting inducible control of the pitRNA, is the first to query the sufficiency of the pitRNA independently. Using quantitative qPCR and targeted bisulfite sequencing, I demonstrated that expression of the lncRNA at physiological levels in the male germline is insufficient to impart DNA methylation at Rasgrf1. These findings were complimented by additional in vitro studies, where I identified Sp1 as a transcription factor that binds the repeats and is required for pitRNA expression. Sp1 binds secondary DNA structure and has recently been identified as a regulating factor at another imprinted gene. Together, these findings support an alternative, critical role for the repeats beyond their known role in regulating pitRNA expression. Beyond mechanism, DNA methylation in the context of disease are an area of active study, though its utility in non-traditional model organisms is nascent. The second focus of my thesis speaks to this. I performed reduced representation bisulfite analysis on two dog breeds with highly diverse morphology and disease risks. While this work is largely preliminary, two differentially methylated regions have direct association with differential disease risk between these two breeds, suggesting that the canine methylome could be used as method of disease surveillance. Advisors/Committee Members: Soloway, Paul (chair), Schimenti, John C. (committee member), Cohen, Paula (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: Genetics; Molecular biology

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APA (6^th Edition):

Chu, E. T. (2017). MECHANISMS AND CONSEQUENCES OF DNA METHYLATION IN TWO MODEL SPECIES. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/59013

Chicago Manual of Style (16^th Edition):

Chu, Erin Tsi-Jia. “MECHANISMS AND CONSEQUENCES OF DNA METHYLATION IN TWO MODEL SPECIES.” 2017. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/59013.

MLA Handbook (7^th Edition):

Chu, Erin Tsi-Jia. “MECHANISMS AND CONSEQUENCES OF DNA METHYLATION IN TWO MODEL SPECIES.” 2017. Web. 06 Mar 2021.

Vancouver:

Chu ET. MECHANISMS AND CONSEQUENCES OF DNA METHYLATION IN TWO MODEL SPECIES. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/59013.

Council of Science Editors:

Chu ET. MECHANISMS AND CONSEQUENCES OF DNA METHYLATION IN TWO MODEL SPECIES. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/59013

Cornell University

6. Brown, Joel. INVESTIGATING MAMMALIAN DEVELOPMENT USING MOUSE FORWARD GENETICS.

Degree: PhD, Genetics and Development, 2018, Cornell University

URL: http://hdl.handle.net/1813/59291

► Forward genetics allows the identification of novel genes involved in a particular biological process. We performed an ENU forward mutagenesis screen in mice aimed at… (more)

▼ Forward genetics allows the identification of novel genes involved in a particular biological process. We performed an ENU forward mutagenesis screen in mice aimed at identifying genes which regulate early organ morphogenesis during development. Fifteen mouse mutants were identified in the screen which possess cardiovascular, craniofacial, extraembryonic, or general body morphology defects. After performing preliminary characterization of all 15 lines, we identified a likely causative mutation in 14 of the 15 mutants. 1D and 13B mutants both exhibit craniofacial defects and were selected for in-depth characterization to identify the molecular mechanisms whereby they regulate embryogenesis. 1D mutants are characterized by an open neural tube in the hindbrain region. This phenotype is similar to human embryos with exencephaly, a congenital birth malformation of high incidence in the human population. Positional cloning of 1D identified a mutation in SPCA1, a Golgi-localized pump that controls calcium homeostasis. Results from the molecular characterization of mouse 1D mutants, as well as from time lapse microscopy of chicken embryos, revealed that calcium is tightly regulated during neural tube closure and that calcium homeostasis is required to promote apical constriction of neuroepithelial cells. These results show that SPCA1 activity is required to regulate the actomyosin dynamics that propel apical constriction, and that the actin severing protein, Cofilin 1, is a key mediator of SPCA1 function. Together, my findings provide the first genetic evidence that calcium homeostasis is needed for neural tube closure, opening a new window into understanding the etiology of human neural tube defects. 13B mutants have neural tube defects accompanied by a suite of other malformations including randomized L-R patterning and maxillary overgrowth. Molecular characterization revealed that all 13B phenotypes result from the absence of cilia, an organelle important for neural tube patterning and for the establishment of L-R asymmetry. Exome sequencing of 13B embryos identified a nonsense mutation in Pibf1. I show that PIBF1 is required for ciliogenesis during early embryonic development and identify a novel role for PIBF1 in regulating centrosome duplication. These findings highlight the importance of PIBF1 in regulating multiple aspects of centrosome biology, and provide a model for understanding how defects in these processes contribute to human ciliopathies. Advisors/Committee Members: Garcia-Garcia, Maria J. (chair), Schimenti, John C. (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: calcium; Actomyosin; Apical Constriction; Cofilin 1; Neural Tube; SPCA1; Developmental biology; Genetics; Molecular biology

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APA (6^th Edition):

Brown, J. (2018). INVESTIGATING MAMMALIAN DEVELOPMENT USING MOUSE FORWARD GENETICS. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/59291

Chicago Manual of Style (16^th Edition):

Brown, Joel. “INVESTIGATING MAMMALIAN DEVELOPMENT USING MOUSE FORWARD GENETICS.” 2018. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/59291.

MLA Handbook (7^th Edition):

Brown, Joel. “INVESTIGATING MAMMALIAN DEVELOPMENT USING MOUSE FORWARD GENETICS.” 2018. Web. 06 Mar 2021.

Vancouver:

Brown J. INVESTIGATING MAMMALIAN DEVELOPMENT USING MOUSE FORWARD GENETICS. [Internet] [Doctoral dissertation]. Cornell University; 2018. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/59291.

Council of Science Editors:

Brown J. INVESTIGATING MAMMALIAN DEVELOPMENT USING MOUSE FORWARD GENETICS. [Doctoral Dissertation]. Cornell University; 2018. Available from: http://hdl.handle.net/1813/59291

Cornell University

7. Chen, Frances. GENOMIC REGULATORY ELEMENTS IN TRANSCRIPTION, DEVELOPMENT, AND DISEASE: GENERATING MOUSE MODELS FOR LATERALITY DEFECTS USING CRISPR/CAS9 GENOME ENGINEERING AT THE PITX2 LOCUS.

Degree: PhD, Comparative Biomedical Sciences, 2018, Cornell University

URL: http://hdl.handle.net/1813/59710

► The genome contains the code of life: conservation of DNA sequence ensures proper stereotypical patterning and precise formation of the body’s tissues replicated in members… (more)

▼ The genome contains the code of life: conservation of DNA sequence ensures proper stereotypical patterning and precise formation of the body’s tissues replicated in members of the same species, while variation in DNA sequence contributes to unique individual and species’ differences in physical form, function, and susceptibility to disease. Genome wide association studies (GWAS) have shown that most sequence variation linked to disease is located not in protein coding genes but in noncoding sequence. The noncoding genome is known to play important roles in regulating chromatin structure and gene expression, and understanding its function will translate to improved understanding of genetic disease and health outcomes. In this dissertation, I have used CRISPR/Cas9 genome editing to perturb noncoding regulatory elements at the critical developmental Pitx2 locus to investigate their function in organogenesis and human disease. The transcription factor Pitx2 patterns the left-right (LR) embryonic axis and regulates LR asymmetric organogenesis. Loss of left-specific Pitx2 expression is linked to life threatening congenital defects of the heart and intestines. Importantly, mutations affecting noncoding sequence upstream of Pitx2 while leaving the Pitx2 gene intact are associated with Pitx2-mediated disease, suggesting that cis-regulatory elements may regulate Pitx2 expression. Here we have investigated differences in chromatin structure and transcription underlying LR asymmetric organogenesis at the Pitx2 locus. We use transcriptional profiling to identify a novel conserved long noncoding RNA, Playrr, that is expressed asymmetric and complementary to Pitx2 and participates in mutually antagonistic transcriptional regulation with Pitx2. In addition to its essential roles in LR organ development, Pitx2 and its genomic locus have been linked to atrial fibrillation (AF), the most common arrhythmia worldwide in humans. Despite multiple GWAS identifying noncoding variants at the Pitx2 locus in association with the most significant genetic contribution to AF risk, the function of these variants and mechanisms by which they may mediate cis-regulation of Pitx2 and AF pathophysiology remain unknown. Here, using CRISPR/Cas9 genome editing in mice to target the Playrr RNA transcript, I demonstrate that Playrr mutant mice have evidence of pacemaker dysfunction and are predisposed to AF, mirroring arrhythmia phenotypes found in Pitx2 loss-of-function mutants and Pitx2 heterozygous mice, suggesting a relationship between Playrr, Pitx2, and AF. In conclusion, my work uncovers a role for the lncRNA Playrr in arrhythmia and provides multiple novel noncoding mouse models to investigate functions of the cis-regulatory genome and the chromatin level mechanisms in the context of Pitx2-related disease. Advisors/Committee Members: Kurpios, Natasza (chair), Soloway, Paul (committee member), Schimenti, John C. (committee member), Fortier, Lisa Ann (committee member).

Subjects/Keywords: LR asymmetry; Pitx2; transcriptional regulation; Developmental biology; Genetics; atrial fibrillation; intestinal morphogenesis; lncRNA

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APA (6^th Edition):

Chen, F. (2018). GENOMIC REGULATORY ELEMENTS IN TRANSCRIPTION, DEVELOPMENT, AND DISEASE: GENERATING MOUSE MODELS FOR LATERALITY DEFECTS USING CRISPR/CAS9 GENOME ENGINEERING AT THE PITX2 LOCUS. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/59710

Chicago Manual of Style (16^th Edition):

Chen, Frances. “GENOMIC REGULATORY ELEMENTS IN TRANSCRIPTION, DEVELOPMENT, AND DISEASE: GENERATING MOUSE MODELS FOR LATERALITY DEFECTS USING CRISPR/CAS9 GENOME ENGINEERING AT THE PITX2 LOCUS.” 2018. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/59710.

MLA Handbook (7^th Edition):

Vancouver:

Chen F. GENOMIC REGULATORY ELEMENTS IN TRANSCRIPTION, DEVELOPMENT, AND DISEASE: GENERATING MOUSE MODELS FOR LATERALITY DEFECTS USING CRISPR/CAS9 GENOME ENGINEERING AT THE PITX2 LOCUS. [Internet] [Doctoral dissertation]. Cornell University; 2018. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/59710.

Council of Science Editors:

Chen F. GENOMIC REGULATORY ELEMENTS IN TRANSCRIPTION, DEVELOPMENT, AND DISEASE: GENERATING MOUSE MODELS FOR LATERALITY DEFECTS USING CRISPR/CAS9 GENOME ENGINEERING AT THE PITX2 LOCUS. [Doctoral Dissertation]. Cornell University; 2018. Available from: http://hdl.handle.net/1813/59710

Cornell University

8. Welsh, Ian. Giving Shape To Genomic Regulatory Networks Controlling Craniofacial And Asymmetric Organ Morphogenesis.

Degree: PhD, Genetics, 2016, Cornell University

URL: http://hdl.handle.net/1813/43625

► Morphogenesis is the most critical and dynamic utilization of genomic information in the life history of an organism and a powerful system for advancing our… (more)

▼ Morphogenesis is the most critical and dynamic utilization of genomic information in the life history of an organism and a powerful system for advancing our understanding of genomic regulation and function. Stereotyped morphogenic processes provide an invaluable system for directly visualizing the functional activity of the genome via our ability to position its operational components relationally in space and time through the techniques of experimental embryology, molecular biology, and transcriptome analysis. Developmental genomics seeks to establish in vivo models to provide a cellular context where the causal relationships between the expression of key morphoregulatory genes, their transcriptional targets, and the morphogenic cellular behaviors that they control are easily determined, quantifiable, and amenable to experimental manipulation. In pursuit of this challenge, I have developed and characterized gene regulatory network models focused on two critical morphogenic processes, craniofacial development and asymmetric organ morphogenesis. Formation of the vertebrate face requires the coordinated outgrowth and fusion of multiple paired prominences. How morphogenetic domains are integrated to coordinate craniofacial development is an important question, and while a number of genes and pathways important for palate development have been identified, an understanding of how these signals are organized and integrated to achieve precise control of craniofacial development has been lacking. My analysis identifies a previously unrecognized growth zone responsible for periodic signaling center formation and the modular organization of developmentally important signaling genes and transcription factors (e.g. Shh, Bmp4, Msx1, and Barx1) in the developing palate. This newly identified growth zone provides a distributed system of common instructional cues that maintain growth of the secondary palate in proper registration with the surrounding elements of the upper jaw. Patterning of the embryonic left-right axis is essential to directing the asymmetric growth and morphology of individual organs. Overall body situs and asymmetry of organ morphology is critical to normal function and regulated by the homeobox transcription factor Pitx2. Importantly however, the gene targets and cellular behaviors controlled by Pitx2 to manifest asymmetry remain obscure. Using transcriptomics of the simple binary left-right organization of the dorsal mesentery (DM), I have elaborated and functionally characterized Pitx2 dependent asymmetric cellular processes acting on very different scales of biological organization. At the tissue level I show that regulation of asymmetric intercellular signaling is a conserved mechanism through with Pitx2 manifests differential cellular behavior to achieve asymmetric organ growth. At the chromatin level, I have leveraged the novel finding that genes physically linked to Pitx2 exhibit complementary right-specific expression relative to left-sided Pitx2 in order to characterized the relationship between 3D… Advisors/Committee Members: Kurpios,Natasza (chair), Schimenti,John C. (committee member), Noden,Drew Morrison (committee member), Lis,John T (committee member).

Subjects/Keywords: genomics; morphogenesis; transcriptional regulation

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APA (6^th Edition):

Welsh, I. (2016). Giving Shape To Genomic Regulatory Networks Controlling Craniofacial And Asymmetric Organ Morphogenesis. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/43625

Chicago Manual of Style (16^th Edition):

Welsh, Ian. “Giving Shape To Genomic Regulatory Networks Controlling Craniofacial And Asymmetric Organ Morphogenesis.” 2016. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/43625.

MLA Handbook (7^th Edition):

Welsh, Ian. “Giving Shape To Genomic Regulatory Networks Controlling Craniofacial And Asymmetric Organ Morphogenesis.” 2016. Web. 06 Mar 2021.

Vancouver:

Welsh I. Giving Shape To Genomic Regulatory Networks Controlling Craniofacial And Asymmetric Organ Morphogenesis. [Internet] [Doctoral dissertation]. Cornell University; 2016. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/43625.

Council of Science Editors:

Welsh I. Giving Shape To Genomic Regulatory Networks Controlling Craniofacial And Asymmetric Organ Morphogenesis. [Doctoral Dissertation]. Cornell University; 2016. Available from: http://hdl.handle.net/1813/43625

Cornell University

9. Bhattacharya, Asmita. ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER.

Degree: PhD, Genetics, Genomics and Development, 2019, Cornell University

URL: http://hdl.handle.net/1813/67493

► Recent literature has revolutionized our view on the patho-physiological importance and the underlying molecular mechanism of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease.… (more)

▼ Recent literature has revolutionized our view on the patho-physiological importance and the underlying molecular mechanism of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease. Aside from being a downstream element of ER stress response or the unfolded protein response (UPR), ERAD also plays a direct and vital role in health and disease, in a substrate-specific and largely UPR-independent manner. The Sel1L-Hrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)-associated degradation (ERAD) machinery. Here, we have focused on the role of ERAD in the liver in the context of energy metabolism, bile homeostasis and cancer pathogenesis. In a recent publication, we reported the discovery of a novel mechanism underlying ERAD-mediated regulation of Fgf21 expression during growth and fasting-feeding. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, leading to massive alterations in growth and systemic metabolic profile. Mechanistically, we show that the Sel1L-Hrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh. This study not only establishes the importance of hepatic Sel1L-Hrd1 ERAD in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERAD-Crebh-Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation. In another study, our data revealed the importance of ERAD in the regulation of bile metabolism, where a deficiency in hepatic ERAD causes significantly impaired secretion of bile acids, cholesterol and phosphatidylcholine into bile, leading to hypercholanemia and extreme sensitivity to dietary bile acid challenge. This occurs due to defective maturation of exporter proteins associated with bile production, owing to faulty ERAD of these proteins. Finally, in a parallel study, we identify and characterize a novel and significant relationship between hepatic ERAD and liver cancer pathogenesis via the Wnt signalling pathway. Here we demonstrate that Sel1L-Hrd1 ERAD in the liver functions to triage the secreted protein Wnt5A during its maturation in the ER. In the absence of ERAD, Wnt5A aggregates and allows unrestrained proliferation of hepatocytes, thereby markedly increasing the propensity to liver cancer development. Taken together, we propose the new concept of “constitutive” or “basal” ERAD and its significance in managing cellular and organismal function, and define novel paradigms underlying ERAD function in both quality and quantity control of proteins synthesized in the ER, and nuclear gene transcription. Advisors/Committee Members: Weiss, Robert S. (chair), Qi, Ling (committee member), Simpson, Kenneth William (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: Fgf21; protein folding; Wnt pathway; Biochemistry; physiology; Molecular biology; ERAD; cancer; bile

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APA (6^th Edition):

Bhattacharya, A. (2019). ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/67493

Chicago Manual of Style (16^th Edition):

Bhattacharya, Asmita. “ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER.” 2019. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/67493.

MLA Handbook (7^th Edition):

Bhattacharya, Asmita. “ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER.” 2019. Web. 06 Mar 2021.

Vancouver:

Bhattacharya A. ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER. [Internet] [Doctoral dissertation]. Cornell University; 2019. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/67493.

Council of Science Editors:

Bhattacharya A. ENDOPLASMIC RETICULUM ASSOCIATED DEGRADATION (ERAD) IN THE LIVER. [Doctoral Dissertation]. Cornell University; 2019. Available from: http://hdl.handle.net/1813/67493

Cornell University

10. Ledet, Melissa McDowell. The Mammary Gland in Health and Disease.

Degree: PhD, Biomedical and Biological Sciences, 2019, Cornell University

URL: http://hdl.handle.net/1813/67458

► The mammary gland is a conserved, defining feature among mammals; however, there is much variation between species in both healthy functions, such as lactation, and… (more)

▼ The mammary gland is a conserved, defining feature among mammals; however, there is much variation between species in both healthy functions, such as lactation, and diseases, such as mammary cancer and mastitis. Species such as the cow, for example, are expert lactators, while lactation insufficiency remains a problem for many women. Mammary cancer is common in species such as humans, dogs and cats, but is rare in other species such as horses, cows and pigs. The majority of this work focuses on mammary stem/progenitor (MaSC) cells as these are the cells thought to drive lactation and to be at least partly responsible for mammary cancer development. These cells have been successfully isolated and characterized in mice, humans, and cows; however, these methods use species-specific antibodies and thus cannot be broadly applied across species. We first describe a novel method for isolating and characterizing MaSC from many different species in an antibody-independent manner. We then describe two projects that use this method for a comparative species approach to define possible underlying mechanisms behind mammary cancer resistance. In the second project we discovered that the secretome of equine MaSC kills a subset of human breast cancer cells, establishing the potential therapeutic effects of the MaSC secretome. With this in mind, we focused on the other primary disease of the mammary gland: mastitis, an inflammatory disease most commonly caused by bacterial infections. We found that the secretome of bovine MaSC repairs epithelial and endothelial cell damage and contains antimicrobial peptides, making it a good option for complementary mastitis therapy. In our final project, we once again demonstrate the advantages of using a comparative species approach to identify potential treatments for canine and feline mammary cancer, modeled after what has previously been described for breast cancer in humans. Collectively, this work denotes two potential mechanisms for cancer resistance in domestic species and highlights the potential therapeutic benefits of the MaSC secretome. Advisors/Committee Members: Van de Walle, Gerlinde (chair), Weiss, Robert S. (committee member), Coonrod, Scott A. (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: Cellular biology

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APA (6^th Edition):

Ledet, M. M. (2019). The Mammary Gland in Health and Disease. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/67458

Chicago Manual of Style (16^th Edition):

Ledet, Melissa McDowell. “The Mammary Gland in Health and Disease.” 2019. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/67458.

MLA Handbook (7^th Edition):

Ledet, Melissa McDowell. “The Mammary Gland in Health and Disease.” 2019. Web. 06 Mar 2021.

Vancouver:

Ledet MM. The Mammary Gland in Health and Disease. [Internet] [Doctoral dissertation]. Cornell University; 2019. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/67458.

Council of Science Editors:

Ledet MM. The Mammary Gland in Health and Disease. [Doctoral Dissertation]. Cornell University; 2019. Available from: http://hdl.handle.net/1813/67458

Cornell University

11. Brown, Jessica. ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING.

Degree: PhD, Comparative Biomedical Sciences, 2017, Cornell University

URL: http://hdl.handle.net/1813/51653

► Extracellular signal-regulated kinase (ERK) signaling is required for function of the hypothalamic-pituitary-gonadal axis. This axis is regulated by interconnected hormonal feedback loops, permitting reproduction. Gonadotropin… (more)

▼ Extracellular signal-regulated kinase (ERK) signaling is required for function of the hypothalamic-pituitary-gonadal axis. This axis is regulated by interconnected hormonal feedback loops, permitting reproduction. Gonadotropin releasing hormone (GnRH) is secreted by the hypothalamus to act on the pituitary, resulting in gonadotropin secretion. The gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) are produced and secreted by pituitary gonadotropes, and act on the gonads, promoting steroidogenesis and gametogenesis. This dissertation focuses on two isoforms of ERK, ERK 1 and ERK 2. Although they do appear to have some redundant functions, ERK 1 is not able to compensate for loss of ERK 2. ERK1 null mice are viable and fertile, whereas loss of ERK2 is embryonic lethal. Therefore, ERK 2 has to be knocked out in a tissue or time dependent manner. For the studies included here, we utilize a mouse model of GnRHR associated ERK loss. This model allows us to investigate the role of ERK in pituitary gonadotropin production and secretion. ERK loss significantly reduced gonadotropin production, and this model allowed us to characterize the effects of hypogonadotropism as animals aged. We followed those studies with an investigation into GnRHR localization and function in the murine placenta, and the effects of ERK loss on placentation, gestation, and parturition. These experiments revealed abnormal histology and vascularization, prolonged gestation and dystocia, and absolute fetal mortality. Finally, we utilized unbiased screening techniques (RNA sequencing) to identify novel targets of GnRH signaling downstream of the ERK cascade. This revealed a bile acid receptor, TGR5, which has a functional role in gonadotropin production in the pituitary. Female TGR5 knockout are subfertile, with a marked delay in the onset of puberty. The studies in this dissertation describe the role of ERK in multiple aspects of the HPG axis. All of the studies have clinical implications, either in the understanding and treatment of idiopathic hypogonadotropic hypogonadism (IHH) or in understanding links between puberty, nutrition, metabolism and fertility. Advisors/Committee Members: Roberson, Mark S (chair), Cohen, Paula E. (chair), Cheong, Soon Hon (committee member), Kurpios, Natasza (committee member), Navratil, Amy M (committee member).

Subjects/Keywords: Placenta; Developmental biology; Biology; Metabolism; ERK; GnRH; pituitary; reproduction

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APA (6^th Edition):

Brown, J. (2017). ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/51653

Chicago Manual of Style (16^th Edition):

Brown, Jessica. “ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING.” 2017. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/51653.

MLA Handbook (7^th Edition):

Brown, Jessica. “ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING.” 2017. Web. 06 Mar 2021.

Vancouver:

Brown J. ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/51653.

Council of Science Editors:

Brown J. ANALYSIS OF GnRH AS A CENTRAL REGULATOR OF FERTILITY: EXPLORING THE MULTIPLE ROLES OF ERK SIGNALING. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/51653

Cornell University

12. Hart, James Charles. A characterization of orofacial phenotypes resulting from tissue specific deletion of Pbx genes within the cranial neural crest cell population or the cephalic epithelium of the developing murine embryo.

Degree: PhD, Comparative Biomedical Sciences, 2018, Cornell University

URL: http://hdl.handle.net/1813/59292

► Affecting approximately 1-in-700 live births, “orofacial clefting” represents the most common class of craniofacial birth defect. Although not a major cause of mortality, these conditions… (more)

▼ Affecting approximately 1-in-700 live births, “orofacial clefting” represents the most common class of craniofacial birth defect. Although not a major cause of mortality, these conditions pose significant problems for those affected, including necessary surgical interventions, psychological difficulty and a higher mortality risk. Epidemiological studies of populations affected by clefting, combined with genetic analyses, have identified candidate genes, genomic regions of interest as well as environmental risk factors. Analyses of these factors in mouse models has provided insight into craniofacial morphogenesis. Concurrently, novel factors, discovered through mouse mutagenesis, have been identified in affected human populations. Using modern imaging techniques, overt clefting has been revealed to be part of larger phenotypic spectrum. For this reason, detailed morphological studies of mouse-mutants with craniofacial phenotypes are necessary for effective modeling and comparisons to be made. The Pbx genes (Pbx 1-2-3), TALE homeodomain-containing transcription factors, are believed to play integral roles in the development of many organ systems including the midfacial complex. By immunofluorescence antibody assay, this study provides the first detailed analyses of how Pbx1 & Pbx2 are expressed temporally and spatially in the developing murine midface, over the developmental time-period critical for development of the lip, primary and secondary palates (E10.5 to E13.5). Pbx1&2 expression was observed in epithelium and mesenchyme from the very earliest stages of facial morphogenesis, and into the later stages of palatal development. Excision of Pbx1 from the cephalic epithelium or pre-migratory Cranial Neural Crest cells revealed highly distinct and temporally divergent phenotypes. For the cephalic epithelial mutant (Pbx1fl/fl ; Pbx2wt, FoxG1Crewt/+), cleft lip, extending into the primary palate with clefting of the secondary palate was the primary observation, whereas Pbx1 excision from premigratory Cranial Neural Crest Cells on a Pbx2 deficient background (Pbx1fl/fl ; Pbx2¬+/-, Wnt1Cretg/+), yielded cleft palate only with a “bridging phenotype” rostrally and palatal shelf hypoplasia. Micro-CT analysis enabled identification of craniofacial elements responsible for the distinct facial/palatal phenotypes. Specifically, the Epithelial Mutant exhibited: 1) an increase in the distance from the incisor alveolus to the caudal basisphenoid; 2) rostro-caudal shortening and widening of the premaxilla; 3) diagonal lengthening of the maxilla; 4) reduction of the maxillary width; and 5) widening of the distance between the zygomatic spurs of the maxillae. The Cranial Neural Crest Cell mutant displayed: 1) rostro-caudal shortening of the cranial base as measured from the basioccipital bone to the incisor alveolus; 2) increase of premaxillary width at both rostral tip and caudal end; 3) shortening and widening of the maxillae; and 4) an increase in the inter-maxillary distance. Although divergent, the morphological outcome in both… Advisors/Committee Members: Selleri, Licia I (chair), Soloway, Paul (committee member), Garcia-Garcia, Maria J. (committee member), Bonassar, Lawrence (committee member), Noden, Drew Morrison (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: Veterinary science; Palate; Cleft; Cranial Neural Crest; Developmental biology; Pbx; Mouse; Molecular biology

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APA (6^th Edition):

Hart, J. C. (2018). A characterization of orofacial phenotypes resulting from tissue specific deletion of Pbx genes within the cranial neural crest cell population or the cephalic epithelium of the developing murine embryo. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/59292

Chicago Manual of Style (16^th Edition):

Hart, James Charles. “A characterization of orofacial phenotypes resulting from tissue specific deletion of Pbx genes within the cranial neural crest cell population or the cephalic epithelium of the developing murine embryo.” 2018. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/59292.

MLA Handbook (7^th Edition):

Vancouver:

Hart JC. A characterization of orofacial phenotypes resulting from tissue specific deletion of Pbx genes within the cranial neural crest cell population or the cephalic epithelium of the developing murine embryo. [Internet] [Doctoral dissertation]. Cornell University; 2018. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/59292.

Council of Science Editors:

Hart JC. A characterization of orofacial phenotypes resulting from tissue specific deletion of Pbx genes within the cranial neural crest cell population or the cephalic epithelium of the developing murine embryo. [Doctoral Dissertation]. Cornell University; 2018. Available from: http://hdl.handle.net/1813/59292

13. Sivakumar, Aravind. THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS.

Degree: PhD, Biochemistry, Molecular and Cell Biology, 2017, Cornell University

URL: http://hdl.handle.net/1813/56744

► THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS Aravind Sivakumar, Ph.D. Cornell University 2017 During embryonic development, organ morphogenesis is… (more)

▼ THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS Aravind Sivakumar, Ph.D. Cornell University 2017 During embryonic development, organ morphogenesis is driven by coordination and alignment of local cellular behaviors with the three body axes: dorsal-ventral (DV), anterior-posterior (AP) and left-right (LR) axes. This involves translation and amplification of molecular chirality defined by genetically encoded spatial cues into asymmetric cell behavior that is critical for defining the organ’s form and function. The gastrointestinal tract, displaying profound LR asymmetries, presents itself as a powerful model to study the asymmetric mechanisms involved in the establishment of its stereotypical looping topology and patterning of its vasculature. Asymmetric looping morphogenesis of the gut initiates with a critical leftward tilt directed by the evolutionarily conserved LR pathway. Failure to do so leads to gut malrotation and the catastrophic midgut volvulus, highlighting an urgent need to define the molecular basis of this process. Previous research in mice and birds has shown that the leftward tilt of the gut is established by cellular and extracellular asymmetries across the LR axis of the dorsal mesentery (DM), which suspends the gut tube. The left DM condenses while the right expands causing the DM to tilt the gut tube leftward, and this critical bias determines gut chirality. Concomitantly, vasculogenesis of the gut proceeds within the left DM but is excluded on the right, suggesting that the cellular processes within the DM are also employed to pattern abdominal blood vessels. While the left DM has been shown to be under the control of the left-determining transcription factor Pitx2, the mechanisms that regulate the expansion and vascular exclusion specific to the right DM have remained unknown. Surprisingly, my research demonstrates that the expansion of the right DM precedes all other cell asymmetries that collectively deform this structure, suggesting that the key initiator of asymmetric gut tilting derives from the right side. Hyaluronan (HA), a unique and highly conserved glycosaminoglycan, predominates in the extracellular matrix (ECM) of the right DM. Targeted degradation of HA in the right DM ablates expansion, gut tilting and results in aberrant retention of vasculature in the right DM. This unexpected finding demonstrates that HA is a critical regulator of the ECM expansion and vascular exclusion necessary for asymmetric gut looping and vascular morphogenesis. Investigating into how HA enacts its functions, I show that the tumor necrosis factor alpha-inducible protein 6 (Tsg6/Tnfaip6), an enzyme that covalently modifies HA to form a stable heavy chain (HC) HA complex, is restricted to the right DM. Knockdown of Tsg6 on the right prevents ECM expansion, gut tilting, and disrupts the normal process of vascular exclusion, leading to aberrant gut vascular patterning. Furthermore, misexpression of Tsg6 in the left DM prevents the formation of abdominal blood vessels… Advisors/Committee Members: Kurpios, Natasza (chair), Liu, Jun (committee member), Butcher, Jonathan T. (committee member).

Subjects/Keywords: Developmental biology; Genetics; Molecular biology; asymmetric morphogenesis; Extracellular Matrix; Gut development; Hyaluronan; organ morphogenesis; vascular development

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APA (6^th Edition):

Sivakumar, A. (2017). THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/56744

Chicago Manual of Style (16^th Edition):

Sivakumar, Aravind. “THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS.” 2017. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/56744.

MLA Handbook (7^th Edition):

Sivakumar, Aravind. “THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS.” 2017. Web. 06 Mar 2021.

Vancouver:

Sivakumar A. THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS. [Internet] [Doctoral dissertation]. Cornell University; 2017. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/56744.

Council of Science Editors:

Sivakumar A. THE ROLE OF HYALURONAN-RICH ECM IN THE REGULATION OF GUT AND VASCULAR MORPHOGENESIS. [Doctoral Dissertation]. Cornell University; 2017. Available from: http://hdl.handle.net/1813/56744

14. Houtz, Philip Lewis. CHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION.

Degree: PhD, Entomology, 2018, Cornell University

URL: http://hdl.handle.net/1813/64869

► The epithelium of the gastrointestinal (GI) tract serves vital roles as both digestive tissue and a barrier against pathogens and other harmful material from the… (more)

▼ The epithelium of the gastrointestinal (GI) tract serves vital roles as both digestive tissue and a barrier against pathogens and other harmful material from the environment. In order to maintain homeostasis, intestinal epithelia must undergo continuous tissue turnover by the activity of dedicated intestinal stem cells (ISCs), which divide to self-renew and differentiate into new epithelial cells. Regulating constant tissue renewal in spite of physical and microbial challenges requires careful coordination by cellular signaling to link the detection of damage or stress with adequate repair. In this thesis, I investigated the regulatory networks controlling intestinal epithelial cell behavior to promote repair of infectious damage in the midgut of Drosophila melanogaster. In both healthy and diseased conditions, pro-regenerative cytokines function as central coordinators of gut renewal, linking inflammation to stem cell activity. In Drosophila, the primary reparative cytokine, Unpaired 3 (Upd3), serves to stimulate the JAK/STAT pathway in epithelial cells in response to pathogenic damage. In the beginning of my PhD, I familiarized myself with the tools and techniques associated with the study of Drosophila midgut repair. The details of these procedures were compiled and published as a chapter in Methods in Molecular Biology, Animal Models for Stem Cell Therapy. I then began an investigation of the regulation of cytokine activity in the Drosophila midgut. I found that the transcriptional activation of upd3 in midgut enterocytes is regulated by the Hippo, Src-MAPK, and TGF-B pathways, which are known to be similarly active in ISCs following enteric damage, and required for subsequent repair responses. This work was published in PLOS Genetics in 2017. Following my findings of the regulatory pathways that initiate epithelial repair in the adult midgut, I investigated how the larval Drosophila midgut, which lacks dedicated ISCs and basal tissue turnover, is able to cope with bacteria-induced damage. Larval Drosophila were found to be more susceptible to infection, and survivors experienced a developmental delay in the onset of pupation. Infected larvae that survive to reach pupation experienced no further delay in their development rate to adult eclosion, and experience no lasting negative impact on their lifespan. I discovered that the larval midgut epithelium was able to undergo limited repair following enteric infection-induced cell loss, by temporary recruitment of adult midgut progenitor (AMP) cells to be differentiated into new enterocytes. Fascinatingly, I found that AMP differentiation in response to epithelial damage is also regulated by Upd3 and the JAK/STAT pathway. In addition to the aforementioned publications, I collaborated with DJ Dutta of Bruce Edgars lab as a middle author in her 2015 Cell Reports paper. Altogether, my work has identified key regulatory networks that act to control epithelial renewal in the GI tract. I have found that JAK/STAT, Notch, EGFR and TGF-B/Dpp signaling pathways are activated… Advisors/Committee Members: Buchon, Nicolas S. (chair), Leifer, Cynthia Anne (committee member), Lazzaro, Brian (committee member), Kurpios, Natasza (committee member).

Subjects/Keywords: Cellular biology; Bacterial infection; Genetic network; Intestinal Stem Cell; Tissue repair; Genetics; Drosophila melanogaster; Entomology

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APA (6^th Edition):

Houtz, P. L. (2018). CHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/64869

Chicago Manual of Style (16^th Edition):

Houtz, Philip Lewis. “CHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION.” 2018. Doctoral Dissertation, Cornell University. Accessed March 06, 2021. http://hdl.handle.net/1813/64869.

MLA Handbook (7^th Edition):

Houtz, Philip Lewis. “CHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION.” 2018. Web. 06 Mar 2021.

Vancouver:

Houtz PL. CHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION. [Internet] [Doctoral dissertation]. Cornell University; 2018. [cited 2021 Mar 06]. Available from: http://hdl.handle.net/1813/64869.

Council of Science Editors:

Houtz PL. CHARACTERIZATION OF MIDGUT EPITHELIAL REPAIR IN ADULT AND LARVAL DROSOPHILA IN RESPONSE TO ENTERIC INFECTION. [Doctoral Dissertation]. Cornell University; 2018. Available from: http://hdl.handle.net/1813/64869

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