Medicine and Health Sciences Commons^™

Retinal Ganglion Cells Underlying Visual Perception And Predation In Mice, Keith Patrick Johnson

Arts & Sciences Electronic Theses and Dissertations

The spike trains of retinal ganglion cells (RGCs) are the sole source of visual information to the brain. In mice, more than 40 RGC types send signals to more than 50 brain areas. RGCs that perform nonlinear operations to extract specific visual features (e.g., the motion of an object against a background) are called feature detectors. Those that linearly integrate local changes in light inten-sity are known as pixel encoders. Most mouse RGC types are feature detectors. In the first part of my dissertation, I discovered a pixel encoder RGC type in mice, the PixON-RGC. I revealed how the unique …

Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir

Arts & Sciences Electronic Theses and Dissertations

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there …

Gut Reactions: Quantitative Predictions Of The Responses Of Human Gut Microbiota To Medical Interventions, Amy Elizabeth Langdon

Arts & Sciences Electronic Theses and Dissertations

The collection of microbes known as the human microbiome perform vital functions for their host, and when this community becomes unhealthy, its dysbiosis is implicated in a myriad of diseases. The gut microbiota in particular are known to suppress colonization of opportunistic pathogens, regulate the immune system, aid in nutrient breakdown, produce vitamins, and a growing number of other functions. In order to intervene in a dysbiotic microbial ecology, we can try to remove unwanted microbes or try to recolonize the gut with microbes expected to be beneficial. This dissertation provides an overview of the state of medical interventions for …

Glial Inflammatory Responses Regulate Neurocognitive Recovery Following Viral Encephalitis, Allison Luen Soung

Arts & Sciences Electronic Theses and Dissertations

The concept of the brain as an immune privileged organ has been slowly shifting as an in-creasing number of studies have demonstrated that even under homeostatic conditions, commu-nication between the nervous and immune system is essential for proper brain function. Given their roles in innate and adaptive immunity, glial cells and infiltrating immune cells have been placed at the center of this communication axis. Microglia, astrocytes, and T cells have all been shown to receive and convey information to all neural cell types in a coordinated effort to re-spond to injury and infection and initiate reparative mechanisms as well as …

Homeostatic T Cell Receptor Interactions With Self-Peptide Tune Cd4+ T Cell Function, Juliet Marie Bartleson

Arts & Sciences Electronic Theses and Dissertations

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function

by

Juliet Marie Bartleson

Doctor of Philosophy in Biology and Biomedical Sciences

Immunology

Washington University in St. Louis, 2021

Professor Paul M. Allen, Chair

Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions …

Visual And Non-Visual Control Of Movement: The Role Of Proprioception In Upper Limb Function After Stroke, Nathan A. Baune

Arts & Sciences Electronic Theses and Dissertations

This dissertation presents a series of studies into human reach and grasp, focusing on the neural systems and behaviors of upper-limb action that underly performance under varied sensory conditions: specifically, acting with and without visual feedback of the limb and under typical or impaired proprioceptive sensation (proprioceptive decline with aging and proprioceptive deficit following stroke). Under typical conditions, a combination of visual and non-visual (e.g., proprioception) sources of information are used to guide action. In the instance of stroke survivors or elderly individuals with proprioceptive deficits/decline, there may be a necessary reliance on visual information to perform. The studies are …

Midfoot And Ankle Movement Dysfunction In People With Diabetes Mellitus And Peripheral Neuropathy, Hyo Jung Jeong

Arts & Sciences Electronic Theses and Dissertations

People with diabetes mellitus and peripheral neuropathy (DMPN) have midfoot and ankle musculoskeletal problems, including limited joint mobility and weakness and atrophy of foot intrinsic and calf muscles. Impaired foot structures and function could lead to midfoot and ankle movement dysfunction, measured by a heel rise task. A repeated movement dysfunction during weightbearing tasks (e.g., heel rise, walking) could cause excessive stress on the plantar tissue, which is a leading cause of plantar ulceration in people with DMPN. Understanding heel rise performance and the underlying mechanisms could help prevent the sequence of events associated with plantar ulcer development in people …

Examining Early Interactions Between Innate Airway Resident Immune Cells And Mtb-Specific Factors During Pulmonary Infection With Mycobacterium Tuberculosis, Micah D. Dunlap

Arts & Sciences Electronic Theses and Dissertations

Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent in the world today, infecting roughly one quarter of humans. Despite this, the mechanisms of early pathogenesis and host protective innate immune responses remain poorly understood and uncharacterized.

Lung resident Alveolar Macrophages (AMs) are the first host contact with Mtb bacilli after inhalation and are thus key mediators of the early pulmonary immune response. AMs are generally believed to reside entirely in the airway, but it was recently demonstrated that they have the capacity to egress and enter into granulomas during pulmonary infection with hypervirulent Mtb. Furthermore, …

Contribution Of Tgf-B Signaling To The Pathogenesis Of Myeloproliferative Neoplasms, Juo-Chin Yao

Arts & Sciences Electronic Theses and Dissertations

TGF-b expression is increased in most cases of myeloproliferative neoplasms (MPNs); however, its contribution to disease pathogenesis is not well understood. Here, we explore two specific hypotheses. First, we hypothesize that increased TGF-b signaling in mesenchymal stromal cells contributes to the development of myelofibrosis. Second, we hypothesize that Jak2 mutated hematopoietic stem cells (HSCs) are resistant to the growth suppressive effect of TGF-b, conferring a fitness advantage that contributes to their expansion in MPNs and clonal hematopoiesis. To test the first hypothesis, we abrogated TGF-b signaling in mesenchymal stem/progenitor cells by deleting Tgfbr2 using a doxycycline-repressible Osterix-Cre transgene (Osx-Cre), which …

Targeting The Phgdh-Mtor Metabolic Axis In Osteosarcoma, Richa Rathore

Arts & Sciences Electronic Theses and Dissertations

Altering cellular energy metabolism has been highlighted as one of the emerging hallmarks of cancer. The reprogramming of bioenergetic pathways towards enhanced glycolysis, rather than the mitochondrial oxidative phosphorylation indicative of normal cells, results in increased biomass production and is associated with the activation of various oncogenes. The increased or decreased expression of key metabolic enzymes has been identified as a potential family of biomarkers that could serve as the targets for novel metabolic-based therapies in cancer.

The serine, glycine, and one-carbon (SGOC) metabolism pathway consists of a series of enzymes and metabolites that drive protein and lipid production, enhanced …

A Mechanistic And Genomic Analysis Of Molluscum Contagiosum Virus Immune Evasion, Ian Benjamin Harvey

Arts & Sciences Electronic Theses and Dissertations

Molluscum contagiosum virus (MCV) is a common human-specific poxvirus with a proclivity for

infecting children and the immune-compromised. A characteristic MCV infection is restricted to

the epidermal layers of the skin and can persist for weeks to years in an otherwise healthy

individual. The high clinical burden of MCV is at odds with our limited knowledge regarding how

it successfully evades the human immune response, which is in part due to the lack of an animal

model or cell line to propagate the virus. Through this dissertation, we have uncovered and

characterized a novel mechanism by which MC80, a protein …

Pathophysiology And Proteogenomics Of Post-Infectious And Post-Hemorrhagic Hydrocephalus In Infants, Albert M. Isaacs

Arts & Sciences Electronic Theses and Dissertations

Post-infectious (PIH) and post-hemorrhagic (PHH) hydrocephalus occur as sequalae of neonatal sepsis or intraventricular hemorrhage (IVH) of prematurity, respectively. Together, PIH and PHH represent the most common form of infantile hydrocephalus, the most common indication for neurosurgery in children globally, and the leading cause of neurological morbidity and mortality worldwide. The lack of understanding of the pathophysiology of PIH and PHH, particularly with regards to the host central nervous system response to the antecedent infection and hemorrhage, perturbation of differentiating neural stems in the ventricular (VZ) and subventricular (SVZ) zones, and damage to periventricular white matter (PVWM) tracts carrying sensorimotor …

Mechanisms Of Cross-Presentation By Cdc1s, Derek James Theisen

Arts & Sciences Electronic Theses and Dissertations

Classical dendritic cells (cDCs) are specialized antigen presenting cells that can be divided into distinct subsets based on the types of pathogens they respond to and the type of immune response they generate. The cDC1 subset is specialized in priming CD8 T cell responses through the process of cross-presentation. During cross-presentation, exogenous protein antigens are taken up by cDC1 and presented on MHCI molecules, allowing for the priming of CD8 T cells during conditions when DCs themselves are not directly infected. The ability to cross-present in vivo is unique to cDC1, and is essential for anti-viral responses and rejection of …

Mechanisms Of Sting-Associated Vasculopathy And Immunodeficiency, Brock Gordon Bennion

Arts & Sciences Electronic Theses and Dissertations

STING N153S in mice and STING N154S in humans cause spontaneous autoimmunity. Specifically, these mutations reduce the numbers of T cells and NK cells, and cause lung disease. However, mice develop perivascular lung inflammation that is distinct from the pulmonary fibrosis observed in human patients. Viral infections are known to exacerbate autoimmunity and foment pulmonary fibrosis. Therefore, we hypothesized that exposure to a virus may influence STING N153S disease in mice. To test this, we infected STING N153S animals with the gammaherpesvirus family member, gHV68, and found that 14 days post infection pulmonary fibrosis was readily observed by histological staining. …

Effects Of Agonistic Anti-Cd137 Antibody On Chikungunya Virus Infection And B Cell Responses, Jun Hong

Arts & Sciences Electronic Theses and Dissertations

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Pathophysiology And Treatment Of Murine Globoid Cell Leukodystrophy, Yedda Li

Arts & Sciences Electronic Theses and Dissertations

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a rapidly progressing, invariably fatal pediatric disorder first described in 1916. Krabbe disease is caused by a deficiency in the lysosomal enzyme, galactosylceramidase (GALC), and is characterized clinically by failure to thrive, limb stiffness, seizures, developmental regression, and death by 2-4 years of age. Galactosylceramidase degrades the cytotoxic glycolipid, galactosylsphingosine (psychosine). In the absence of GALC activity, psychosine accumulates primarily in oligodendrocytes and Schwann cells, resulting in profound demyelination. In 1972, psychosine was hypothesized to be responsible for the clinical signs associated with Krabbe disease. However, the ‘Psychosine Hypothesis’ has never been …

Phantoms To Placentas: Mr Methods For Oxygen Quantification, Kelsey Meinerz

Arts & Sciences Electronic Theses and Dissertations

Molecular oxygen (O2) is vital for efficient energy production and improper oxygenation is a hallmark of disease or metabolic dysfunction. In many pathologies, knowledge of tissue oxygen levels (pO2) could aid in diagnosis and treatment planning. The gold standard for pO2 measures in tissue are implantable probes, which are invasive, require surgery for placement, and are inaccessible to certain regions of the body. Methods for determining pO2 both non-invasively and quantitatively are lacking. The slight paramagnetic nature of O2 provides opportunities to non-invasively characterize pO2 in tissue via magnetic resonance (MR) techniques. As such, O2 can be treated as a …

Dismantling Of Obesity-Related Policies, Alexandra Borosova Morshed

Arts & Sciences Electronic Theses and Dissertations

This dissertation fills an important research gap in the study of obesity policymaking by characterizing to what extent the phenomenon of dismantling is happening at the state level for obesity-related policies targeting the context of consumption, identifying determinants, and characterizing actors and processes involved. The five-year rate of dismantling of these policies is close to one-third for any attempts and one-tenth for enacted dismantling. Food and beverage tax policies face a particularly high rate of dismantling. Case studies and news coverage of state- level dismantling identified actors, motivations, and strategies used in the process of dismantling. Review of health-related empirical …

Transdiagnostic Multimodal Neural Correlates Of Psychosis Dimensions, Dov Bernard Lerman-Sinkoff

McKelvey School of Engineering Theses & Dissertations

Psychosis refers to a debilitating set of symptoms that impacts individuals, their communities, and society at large. Current psychiatric nosology treats psychosis as a categorical construct. However, recent evidence suggests that a dimensional approach that cuts across extant nosological boundaries may more accurately represent the underlying phenomena contributing to dysfunction in psychosis. One putative domain of transdiagnostic variation is cognitive control, a construct that refers to the set of functions that enable and support goal-directed behavior and regulation of one’s thoughts and actions. Previous analyses in both healthy individuals and individuals with psychosis have led to a number of findings …

Electrophysiology Of The Inner Retina In Health And Disease: Eaat5 In The Rod Bipolar Cell And Oscillatory Potentials In Diabetes, Gregory William Bligard

Arts & Sciences Electronic Theses and Dissertations

The inner retina is a highly tractable location for the study of neural networks in the central nervous system and improving our understanding of the inner retina is important for the treatment of a number of ophthalmic diseases. This dissertation aims to improve understanding of the inner retina in two parts: first, a basic neuroscientific project concerning normal neuronal processing in the inner retina at a cellular level, and second, a translational ophthalmologic project regarding the development in the inner retina of a common disease. In mammals, modulation of the amplitude of dim visual signals primarily occurs at axon terminals …

Dendritic Cell Development And Function, Vivek Durai

Arts & Sciences Electronic Theses and Dissertations

Dendritic cells (DCs) are a group of immune cells that include both classical dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). cDCs are further comprised of two distinct subsets, cDC1s and cDC2s, which play critical roles in the initiation of innate and adaptive immune responses. Understanding how these lineages develop and function is therefore paramount. All DCs require the receptor tyrosine kinase Flt3 and its ligand Flt3L for their development, but the loss of Flt3L in mice leads to a more severe DC deficiency than does the loss of Flt3. This has led to speculation that Flt3L can bind to …

Pillars Of The Nutrition Transition: The Global Impacts Of Ultra-Processed Foods And Beverages On Overweight And Obesity And National Nutrient Supplies, Jacob Eaton

Arts & Sciences Electronic Theses and Dissertations

Malnutrition in some form impacts nearly one-third of the global population. Across the world, countries are undergoing the Үutrition transitionӠfrom traditional and largely unprocessed diets to Western-style, energy-dense diets. At the same time, rates of overweight and obesity and diet-related chronic diseases continue to climb. Ultra-processed foods (UPF), sugar-sweetened beverages (SSB), and vegetable oils are three of the foods driving the nutrition transition. This dissertation calculates changes in the global food supply between 1961 and 2013 and quantifies the influence of UPF and SSB (as measured through sales) on national nutrient supplies between 2005 and 2013 and trends in adult …

In Vivo Mechanisms Of Natural Killer Cell Tolerance, Michael Bern

Arts & Sciences Electronic Theses and Dissertations

Natural killer (NK) cells are cytotoxic innate immune cells that provide protection from pathogens and tumors. To carry out these functions, NK cells must distinguish between healthy and unhealthy self-cells. Inability to recognize stressed cells would lead to a failure of NK-cell immunity whereas inability to identify healthy cells could lead to NK-cell autoimmunity. It remains unclear, however, how NK cells are able to distinguish healthy and unhealthy self-cells with a limited repertoire of germline-encoded receptors. The "missing-self" hypothesis proposes that NK cells identify stressed cells by their reduced expression of MHC class I (MHC-I) that is almost ubiquitously expressed …

Cognitive Recovery In The Post-Infectious Cns, Charise Joy Garber

Arts & Sciences Electronic Theses and Dissertations

Neuroinflammation plays a pivotal role in a variety of diseases of the CNS associated with cognitive impairment, including Alzheimerճ Disease, Parkinsonճ Disease with dementia, Multiple Sclerosis, anti-NMDA receptor encephalitis, and West Nile Virus Neuroinvasive disease (WNND). Despite strong evidence that infiltration of peripheral immune cells and activation of resident microglia and astrocytes occurs in these various diseases, very little is known about how this altered immune environment may influence normal cognitive function. Given that communication between the nervous and immune system is essential for normal cognitive function, the central motivation of my thesis work is to understand the mechanisms by …

Rhythmic Auditory Cueing Of Gait In Parkinson Disease, Adam Patrick Horin

Arts & Sciences Electronic Theses and Dissertations

Parkinson disease (PD) is a neurodegenerative movement disorder characterized by motor complications such as gait deficits and is caused by the depletion of dopamine producing neurons in the basal ganglia (BG). Gait deficits, including decreased velocity and increased variability, are among the most debilitating symptoms of PD and lead to an increased risk of falls. Common pharmacological treatments do not target many gait symptoms. Therefore, gait rehabilitation methods that can improve these deficits in gait are highly important. A common form of gait rehabilitation is known as rhythmic auditory cueing, in which an individual matches their footfalls to the beat …

The Role Of Apolipoprotein E In Alzheimer Disease: From Therapy To Mechanism, Tien-Phat Vuong Huynh

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with irreversible damage to the brain, which manifests in cognitive dysfunction, memory loss, and eventual death. The pathological hallmarks of AD are amyloid plaques, which are cerebral aggregates consisting of fibrils of the amyloid β-protein (Aβ), and filamentous lesions of the microtubule-associated protein tau known as neurofibrillary tangles. In the early 1990s, the apolipoprotein E (apoE) was found to co-localize with amyloid plaques. The ε4 allele of the APOE gene was sequentially identified as the strongest genetic risk factor for AD, increasing the risk by 4 – 12-fold, whereas the ε2 allele …

Understanding The Molecular Pathogenesis Of Retinal Neurodegeneration, Jonathan B. Lin

Arts & Sciences Electronic Theses and Dissertations

Retinal degenerative diseases are a major cause of morbidity in modern society because visual impairment significantly decreases the quality of life of patients. A significant challenge in treating retinal degenerative diseases is their genetic and phenotypic heterogeneity. Furthermore, limitations in our understanding of disease pathophysiology have led to reliance on therapies that often treat disease endpoints rather than addressing disease etiology and/or pathophysiology. The long-term goal of my thesis research was to provide molecular and cellular insights into the pathophysiology underlying diverse retinal degenerative diseases, which may lead to much-needed, novel therapeutic approaches. During the first part of my thesis …

Metabolic Requirements Of Nk Cell Responses To Viral Infection, Annelise Yoo Mah-Som

Arts & Sciences Electronic Theses and Dissertations

In recent years, the field of immunometabolism – the study of how specific changes in cellular metabolism regulate the function of diverse immune cell types—has grown exponentially. Several in vitro studies have examined the metabolic regulation of natural killer (NK) cells, which are first responders for viral infection and malignant transformation; however, much less is known regarding the role of metabolism in directing NK cell responses in vivo, such as during viral infection. In order to examine how NK cell antiviral function is regulated in vivo, we used a wellcharacterized infection with murine cytomegalovirus (MCMV) to assess NK cell cytokine …

Effects Of Toxoplasma Gondii Infection On Nk Cells And Ilc1s, Eugene Park

Arts & Sciences Electronic Theses and Dissertations

Natural killer cells and Type I innate lymphoid cells (ILCs) are subsets of ILCs. In C57BL/6 mice, they share expression of the surface markers NK1. 1 and NKp46, and can produce the cytokine interferon-gamma. These similarities led to the initial classification of natural killer cells and Type I ILCs together under the category of Group 1 ILCs. However, more recent studies found that natural killer cells and ILC1s develop from distinct progenitor cells and utilize transcription factor in distinct manners. Whereas ILC1s require Tbet for their development and are Eomes-independent, natural killer cells require Tbet only for terminal maturation and …

The Enzymatic Function Of The Tir Domain: From Axon Degeneration To Innate Immunity, Kow Essuman

Arts & Sciences Electronic Theses and Dissertations

The Toll/Interleukin-1 Receptor (TIR) domain is an evolutionarily ancient protein domain conserved from bacteria to eukaryotes, and is an essential signaling component of innate immunity pathways. In animal innate immunity, TIR domains have primarily been described for their scaffolding function in assembling protein complexes in host defense. In plant immunity, TIR domains are key components of the intracellular Nucleotide Binding Leucine rich repeat (NLR) immune receptors that confer resistance to pathogens. These NLR receptors trigger cell death and an immune response upon activation, but their mechanism has remained elusive. In bacteria, TIR domain proteins have been suggested to function as …