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Kdm6b Is Required For Self-Renewal Of Normal And Leukemic Mouse Stem Cells Under Proliferative Stress, Cates Mallaney

Arts & Sciences Electronic Theses and Dissertations

KDM6B (JMJD3) is one of two known epigenetic modifiers responsible for the removal of the repressive histone mark, histone-3 lysine-27 trimethylation (H3K27me3), and has been shown to play a role in development, differentiation, and inflammatory stress response. Unlike the other H3K27me3 demethylase, UTX (KDM6A), which is frequently mutated in hematopoietic malignancies, KDM6B is upregulated in a myriad of blood disorders. This suggests that it may have important functions in the pathogenesis of hematopoietic cancers. Here, we examined the role of Kdm6b in hematopoietic stem cell (HSC) fate decisions under normal and malignant conditions to evaluate its potential as a therapeutic …

The Role Of Membrane Excitability In Insulin Regulation, Christopher Howard Emfinger

Arts & Sciences Electronic Theses and Dissertations

In mammals, ATP-sensitive K+ (KATP) channels are essential regulators of insulin secretion from pancreatic islet [beta]-cells, illustrated by the finding that gain-of-function mutations in KATP channels (KATP-GOF) cause neonatal diabetes mellitus (NDM). However, variability in symptom severity and effectiveness of treatment is seen in NDM, even for those with the same mutation and in the same family. Short-term treatment of mice expressing KATP-GOF mutations in [beta]-cells (KATP-GOF mice) with the KATP blocker glibenclamide during disease onset results in two outcomes: one subset becomes severely diabetic (non-remitters), whereas the other subset remains below the glucose levels at which significant side effects …

Biological And Behavioral Mechanisms Underlying Childhood Physical Abuse And Age-Related Disease: Borderline Personality Pathology And Inflammation, Christina Rae Di Iorio

Arts & Sciences Electronic Theses and Dissertations

Background: The frequent comorbidity of psychiatric and physical health conditions may be partially attributable to early life stress-related changes in inflammatory signaling and behavior (e.g., borderline personality pathology, health behaviors) that reciprocally maintain and enhance their effects on overall health.

Methods: Using data from older adults (n=1,630) who participated in the ongoing longitudinal St Louis Personality and Aging Network (SPAN) study, we examined associations between childhood physical abuse, borderline pathology, inflammation markers (i.e., interleukin 6, c-reactive protein), health behaviors, and physical health. Morning fasting serum IL-6 and CRP were assayed from a subset of participants (n=791). Borderline pathology factor scores …

Transcriptional Signatures Of Host Susceptibility In Urinary Tract Infections, Lu Yu

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTI) caused by uropathogenic Escherichia coli (UPEC) are common and highly recurrent. Two important non-behavioral risk factors for UTI in women are genetics and history of two or more episodes of previous UTI. However, specific mechanisms of how these two factors modulate host susceptibility to UTI remain unclear. Concordantly, inbred mice of various genotypes and with different infection histories exhibit different susceptibilities to acute and chronic bladder infection (cystitis), which recapitulates a range of clinical UTI outcomes observed in women. Early host-pathogen interactions have been shown to determine UTI outcomes in mouse models. Here, we used two …

Negative Regulators Of Colonic Peripheral Regulatory T Cell Development, Teresa Lei Ai

Arts & Sciences Electronic Theses and Dissertations

Peripheral Treg cells (pTreg cells) maintain immune homeostasis at mucosal interfaces, where they can develop upon activation of naïve CD4+ T cells by bacteria antigen. However, the cellular and molecular requirements that govern their differentiation in inflamed and homeostatic contexts require further elucidation. To circumvent uncertainties in existing methods of distinguishing pTreg cells from thymic Treg cells (tTreg cells), we analyzed monoclonal cell populations of CT2 and CT6 transgenic (Tg) cells that develop into pTreg cells in response to different species of endogenously presented Helicobacter antigen. In our comprehensive assessment of multiple intestinal inflammatory models, including infections and physical injury, …

Tumors Interrupt Irf8-Mediated Dendritic Cell Development To Overcome Immune Surveillance, Melissa Ann Meyer

Arts & Sciences Electronic Theses and Dissertations

Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, which expands immune suppressive granulocytes and monocytes to create a protective tumor niche shielding even antigenic tumors. As myeloid cells and immune-stimulatory conventional dendritic cells (cDCs) are derived from the same progenitors, it is logical that tumor-induced myelopoiesis might also impact cDC development. The cDC subset cDC1 is marked by CD141 in humans and CD103 or CD8α in mice. cDC1s act by cross presenting antigen and activating CD8+ T cells. Given these functions, CD103+ cDC1s can support anti-tumor CD8+ T cell responses. However, CD103+ cDC1 numbers are …

Bridging The Translational Gap Between Rodent And Human Pain Research, Tayler Diane Sheahan

Arts & Sciences Electronic Theses and Dissertations

The treatment of chronic pain is an immense clinical and societal burden rooted in the ineffectiveness and adverse side effects of existing analgesics. Extensive efforts have been directed towards the development of novel pain therapies with maximal efficacy and minimal unwanted effects; however, putative therapeutic targets identified in preclinical rodent models rarely translate in clinical trials. The poor translational record of basic pain research findings has been attributed, in part, to the use of suboptimal rodent pain models and behavioral endpoints used to assess putative analgesics, as well as differences in the pharmacological profiles of rodents and humans. The work …

The Role Of Tmem178 In Regulation Of Osteo-Immune Activation And Inflammatory Bone Loss, Corinne Elaine Decker

Arts & Sciences Electronic Theses and Dissertations

Pathological bone loss in human disease such as arthritis is largely due to excessive osteoclast recruitment as a consequence of localized inflammation. Innate immune cells, namely neutrophils and macrophages, infiltrate the joint space and release pro-inflammatory cytokines as well as proteases to drive local tissue damage and inflammation. Importantly, IL-1 and TNF-a in particular act on the synovial fibroblasts as well as directly on osteoclast precursors to potently augment osteoclast differentiation and thus bone resorption. Current therapeutics to treat pathological bone loss are widely unsuccessful at targeting both the resorptive and inflammatory components of disease. We have previously demonstrated that …

Physical Activity And Maternal And Neonatal Outcomes In Obese Pregnant Women, Rachel Ann Tinius

Arts & Sciences Electronic Theses and Dissertations

Maternal obesity and physical inactivity during pregnancy are independently associated with unfavorable maternal and neonatal metabolic outcomes. Previous research in non-gravid adults suggests physical activity provides protection from many chronic diseases irrespective of body weight. The primary purposes of this dissertation were to determine the impact of obesity on maternal metabolic health (lipid metabolism, inflammation, insulin resistance) and neonatal metabolic health (adiposity, inflammation, insulin resistance), and to determine if adverse maternal and neonatal metabolic health is improved in obese pregnant women who are physically active during pregnancy compared to sedentary obese women. The secondary purpose of this dissertation was to …

Assessing Vascular Inflammation With Bioluminescence Imaging, Reece Joseph Goiffon

Arts & Sciences Electronic Theses and Dissertations

Cardiovascular disease (CVD) is the leading cause of morbidity, mortality, and health care costs in the developed world and is often undiagnosed until clinical presentation with a major adverse cardiovascular event (MACE). Plasma myeloperoxidase (MPO) content is an emerging biomarker for risk, progression, and prognosis at different stages of CVD. Enzyme-linked immunosorbent assays (ELISAs) are currently used to measure clinical plasma MPO concentration, but ELISAs are costly and time-intensive. Luminol is a chemiluminescent compound with specificity for MPO activity in vivo, but is not sensitive enough for use as a bioluminescence reporter of plasma MPO oxidation. The luminol derivative L-012 …

Assessing Optic Neuritis In A Mouse Model Of Multiple Sclerosis With Diffusion Mr Imaging, Chia-Wen Chiang

Arts & Sciences Electronic Theses and Dissertations

Optic neuritis (ON) is an early manifestation in patients of multiple sclerosis (MS), typically resulting in visual dysfunction. The inflammatory demyelination of the optic nerve in ON closely resembles pathologies of the rest of central nervous system (CNS) white matter in MS. Since accumulated axonal degeneration in MS was considered as the potential cause leading to permanent disability, correlating optic nerve pathology and visual function in ON could be a model system to investigate the relationship between functional outcome and neuropathology. It may also present a new way to reflect the disease progression in MS. Various MR techniques have been …