Life Sciences Commons^™

Genetic Risk Factors For Neurodevelopmental Disorders: Insights From Hipsc-Cerebral Organoids, Michelle L. Wegscheid

Arts & Sciences Electronic Theses and Dissertations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder (NDD) characterized by remarkable phenotypic variability, where affected children manifest a spectrum of central nervous system (CNS) abnormalities, including brain tumors, impairments in attention, behavior, learning disabilities, and an increased incidence of autism spectrum disorder (ASD). A significant barrier to the implementation of precision medicine strategies for children with NF1 is a lack of prognostic risk factors to guide clinical management. However, emerging population-based genotype-phenotype association studies have suggested that the germline NF1 gene mutation may represent one clinically actionable risk factor for NF1-associated neurodevelopmental abnormalities. As a critical step in …

Regional Reprogramming And The Small Intestine: Analysis And Modeling Of Adaptive Regeneration Of The Epithelium, Sarah Elizabeth Waye

Arts & Sciences Electronic Theses and Dissertations

The small intestine in homeostasis is capable of regular regeneration, but in cases of massive injury like Short Bowel Syndrome, the innate human response often fails to fully compensate for the loss of nutrient absorptive surface area that accompanies bowel resection. Murine models display an active compensatory reaction deemed “adaptation” in which the surface area of the bowel is increased to accommodate nutrient absorptive needs. This observation has highlighted several gaps in knowledge regarding bowel adaptation. Firstly, what occurs on a molecular level in murine models during adaptation? Secondly, how can the findings in mice be applied to humans in …

Human Ipsc Tissue-Engineered Cartilage For Disease Modeling Of Skeletal Dysplasia-Causing Trpv4 Mutations, Amanda R. Dicks

McKelvey School of Engineering Theses & Dissertations

Cartilage is essential to joint development and function. However, there is a variety of cartilage diseases, ranging from developmental (e.g., skeletal dysplasias) to degenerative (e.g., arthritis), in which treatments and therapeutics are lacking. For example, specific point mutations in the ion channel transient receptor potential vanilloid 4 (TRPV4) prevent proper joint development, leading to mild brachyolmia and severe, neonatally lethal metatropic dysplasia. Tissue-engineered cartilage offers an opportunity to elucidate the underlying mechanisms of these cartilage diseases for the development of treatments. Human induced pluripotent stem cells (hiPSCs) are an improved cell source option for cartilage tissue engineering given their minimal …

Exploring Β-Cell Function And Heterogeneity In Obese Sm/J Mice, Mario Alejandro Miranda

Arts & Sciences Electronic Theses and Dissertations

Pancreatic β-cells perform glucose-stimulated insulin secretion, a process required to maintain systemic glucose homeostasis. Obesity promotes glycemic and inflammatory stress, causing β-cell death and dysfunction, resulting in diabetes. Efforts to improve β-cell function in obesity have been hampered by observations that β-cells are highly heterogeneous, varying in morphology, function, and gene expression. There is great need to understand the breadth of β-cell heterogeneity in health and obesity to improve diabetic therapies.High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we show that as they resolve hyperglycemia, obese SM/J …

Metabolic Control And Immune Barriers Of Hematopoietic Stem Cells, Hannah Pizzato

Arts & Sciences Electronic Theses and Dissertations

Hematopoietic stem cells (HSCs) have the unique ability to self-renew for life, to differentiate into mature blood lineages, and to readily engraft upon intravenous transplantation. As such, they are the only types of stem cells in routine clinical use. Understanding HSCs and hematopoietic development can provide many lessons for other types of stem cells as they near clinical utility. Through bone marrow transplantation, it was discovered that cells exist with regenerative potential. This led to the search to purify these cells and to determine the function of other hematopoietic cells. By isolating and transplanting cells expressing different combinations of surface …

Investigating The Differentiation And Functional Maturation Of Stem Cell-Derived Β Cells, Leonardo Velazco-Cruz

Arts & Sciences Electronic Theses and Dissertations

Diabetes mellitus is a chronic and global disease rapidly growing in prevalence. Diabetes can be characterized by the dysfunction or death of the glucose sensing insulin secreting  cell.  cells are located within the islet of Langerhans (islet), a tissue within the pancreas. Human islets are critical for the study and treatment of diabetes. However, they can only be obtained from cadaveric organ donors. These cadaveric islets do not proliferate and can only be maintained in vitro for short periods of time, making their availability rare and fleeting. Stem cell-derived -like cells can be generated in indefinite amounts and …

Testing Janzen’S Physiological Barrier Hypothesis Through Experimental Evolution And Biogeographic Studies On Sister Species Pairs, Vincent John Fasanello

Arts & Sciences Electronic Theses and Dissertations

Background: Janzen’s physiological barrier hypothesis suggests that variation in the effectiveness of physiological barriers to dispersal underlies global patterns of speciation and biodiversity. He noted that because a species’ physiology often evolves to match the range of conditions it has experienced in evolutionary history, it is likely that lineages that occupy habitats with wider ranges of temperature variation will tend to be better at dispersing across thermal gradients and will therefore be less likely to speciate as a result of mountain barriers. Despite decades of research into different aspects of this fundamental hypothesis, its assumptions and predictions remain largely untested. …

The Genetic Basis Of Adaptation To Environmental Stress In Two Grass Genomic Model Systems, David Mitchell Goad

Arts & Sciences Electronic Theses and Dissertations

Plants are exposed to a wide variety of environmental stress in the wild and have developed an equally diverse set of adaptations to tolerate them. The evolutionary processes that have led to this functional diversification, and the specific genes and physiological mechanisms involved, are of immense interest to both evolutionary biologists and crop breeders. In this dissertation I investigate adaptation to different types of environmental stress in two economically important grass species, seashore paspalum (Paspalum vaginatum Sw.) and rice (Oryza sativa L.).

Seashore paspalum is a halophytic turfgrass that occupies habitats which can dramatically differ in salt concentration. Populations may …

Transcriptional Control Of Dendritic Cell Function And Development, David Alexander Anderson Iii

Arts & Sciences Electronic Theses and Dissertations

Dendritic cells (DCs) are innate immune cells of the myeloid lineage that are specialized at pathogen recognition, cytokine production, and antigen presentation. Their functions and developmental pathways are largely conserved between mice and humans and mice. The DC lineage is composed of two major subsets, known as plasmacytoid DCs (pDCs) and classical DCs (cDCs). Research conducted to date suggests that the function of pDCs, limited to viral antigen recognition and type I interferon production, can be compensated by other immune cell lineages. On the other hand, there is a consensus that diversified subsets cDCs in mice and humans are essential …

Regulation Of Genome Architecture By Chromatin Remodeling In The Brain, Jared Vega Goodman

Arts & Sciences Electronic Theses and Dissertations

Brain development requires exquisite control of gene expression to establish and refine the proper circuitry of the nervous system. Gene expression control is under the purview of several cellular processes, including chromatin regulation in the form of DNA modification, histone modification, and nucleosome remodeling. Chromatin remodeling enzymes are the major effectors of nucleosome remodeling. These enzymes are clearly involved in brain development – mutations in chromatin remodeling enzymes are likely causative for neurodevelopmental disorders of cognition. Chromatin remodeling enzymes have discrete molecular functions and binding profiles and similarly control distinct phases of nervous system maturation. Chd4 is a Chd family …

The Role Of Cd53 In Hematopoietic Development, Stress, And Malignancy, Zev Joshua Greenberg

Arts & Sciences Electronic Theses and Dissertations

For a cell to function properly, it must be able to interact with and respond to environmental cues; however, expression of surface molecules, proteins, and receptors is not always sufficient to execute a cellular response. Proper organization of the plasma membrane is necessary to facilitate these highly regulated protein interactions, such that a cell can respond to stressors, growth factors, and other signaling molecules. Tetraspanins are a family of transmembrane proteins which help correctly orient surface molecules on the cell membrane, often through tetraspanin enriched microdomains, a membrane structure similar to lipid rafts. As a family, tetraspanins are known to …

The Phylogeography Of Rare Central Tennessee Glade Endemics Trifolium Calcaricum And Viola Egglestonii, Rachel Ann Lyman

Arts & Sciences Electronic Theses and Dissertations

Endemic species are range-restricted to a particular type of habitat and generally occur in a few small populations. Often endemic species are threatened or endangered due to their geographic isolation and limited habitat breadth. Despite the fact that understanding factors that may have shaped the evolutionary history of a species with a narrow distribution can provide important insights for their management and conservation, little is known about the historical forces that gave rise to many endemic species. Endemic species can arise because of factors such as variation in climate, geographic barriers, and habitat specificity, or the combination of several of …

Stem Cell Models To Study The Regulation Of Human Cortical Development And Its Disruption In Neurodevelopmental Disorders, Emily Megan Alexandra Lewis

Arts & Sciences Electronic Theses and Dissertations

Abstract of the DissertationStem Cell Models to Study the Regulation of Human Cortical Development and Its Disruption in Neurodevelopmental Disorders by Emily M. A. Lewis Doctor of Philosophy in Biology and Biomedical Sciences Developmental, Regenerative, and Stem Cell Biology Washington University in St. Louis, 2021 Professor Kristen L. Kroll, Chair

The cell state transitions that occur during complex processes, such as development of the human brain, require precisely controlled changes in gene expression. Major regulators of these developmental events include transcription factors (TFs), which bind the genome in a sequence-specific manner, as well as chromatin modifying proteins and complexes that …

Understanding The Roles Of Dna Methylation And Mecp2 In Neuronal Enhancer Control, Adam Clemens

Arts & Sciences Electronic Theses and Dissertations

The development of organisms relies on complex spatial and temporal patterning of gene expression to define cell types and facilitate their functions. Cis-regulatory elements in our genome are responsible for the control of gene expression across tissues and cell types. Regulation of these elements themselves depends on a balance of activation and repression through epigenetic modifications and molecular regulatory components. Disruption of cis-regulatory element control is emerging as a cause of neurodevelopmental disease. An important contributor to gene regulation in development is methylation of cytosine in DNA, disruption of which has been associated with disease. Notably, while all cell types …

The Role Of Mature Secretory Cells In Gastrointestinal Regeneration, Megan Deanna Radyk

Arts & Sciences Electronic Theses and Dissertations

Differentiated cells exhibit the ability to adjust their cell fate and become more progenitor-like after wide-scale tissue injury. This inherent cell plasticity is shown across many tissues and organisms and is a conserved behavior that ensures organ function even in a chronic injury setting. At the tissue level, the change in cell fate from a differentiated cell to one with more progenitor properties can be identified as metaplasia. Importantly, metaplasias, like Spasmolytic Polypeptide-Expressing Metaplasia (SPEM) in the stomach and Acinar-to-Ductal Metaplasia (ADM) in the pancreas, are risk factors for the development of adenocarcinoma. Thus, understanding the cellular and molecular mechanisms …

Differentiating Human Embryonic Stem Cells In Micropatterns To Study Cell Fate Specification And Morphogenetic Events During Gastrulation, Kyaw Thu Minn

McKelvey School of Engineering Theses & Dissertations

During mammalian embryogenesis, the first major lineage segregation occurs when embryonic epiblast, and extraembryonic trophectoderm and hypoblast arise in the blastocyst. In the next fundamental and conserved phase of animal embryogenesis known as gastrulation, extraembryonic cells provide signals to epiblast to instruct embryonic patterning, and epiblast gives rise to germ layers ectoderm, mesoderm, and endoderm, that will establish all embryonic tissues. Proper specification and morphogenesis of germ layers during gastrulation is vital for correct embryonic development. Due to ethical and legal restrictions limiting human embryo studies, human gastrulation is poorly understood. Our knowledge of human gastrulation has largely been derived …