Medicine and Health Sciences Commons^™

Effects Of Traumatic Brain Injury On The Intestinal Tract And Gut Microbiome, Anthony Desana

Theses and Dissertations--Physiology

Traumatic brain injury (TBI) initiates not only complex neurovascular and glial changes within the brain but also pathophysiological responses that extend beyond the central nervous system. The peripheral response to TBI has become an intensive area of research, as these systemic perturbations can induce dysfunction in multiple organ systems. As there are no approved therapeutics for TBI, it is imperative that we investigate the peripheral response to TBI to identify targets for future intervention. Of particular interest is the gastrointestinal (GI) system. Even in the absence of polytrauma, brain-injured individuals are at increased risk of suffering from GI-related morbidity and …

Alzheimer’S Disease Genetics And Short-Chain Fatty Acid Treatment In Studies Of The Murine Gut Microbiome, Diana Zajac

Theses and Dissertations--Physiology

Elucidating the relationship of the gut microbiome in Alzheimer's Disease (AD) risk and pathogenesis is an area of intense interest. Since 60 to 80% of AD risk is related to genetics and APOE alleles represent the most impactful genetic risk factors for AD, their mechanism(s) of action are under intense scrutiny.

First, I conducted a study on APOE targeted replacement mice to investigate the impact of APOE alleles on the murine gut microbiome. The relative abundance of bacteria from the family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of the class Erysipelotrichia increased with APOE4 status, …

Clinical And Biological Factors Determine Spinal Cord Injury Outcomes: Liquor To Lipids, Ethan Glaser

Theses and Dissertations--Physiology

Spinal cord injuries (SCI) are debilitating and life altering events that can lead to permanent motor and sensory loss. SCI outcomes are impacted by both clinical factors such as blood alcohol content (BAC) at the time of injury as well as biological factors like the lipid-rich myelin debris that accumulates in the injury site. Both clinical and biological factors contribute to SCI recovery, impacting neuroinflammation, locomotor recovery, and histopathology. The purpose of the studies described here is to investigate the role of acute alcohol intoxication and intracellular lipid processing pathways on SCI outcomes in a rodent model.

An elevated BAC …

An Investigation Of Hhv6'S Impact On The Cognitive Progression And Microglial Changes In An Alzheimer's Disease Cohort, Charles E. Seaks

Theses and Dissertations--Physiology

The role of herpesviruses and, more specifically, HHV6 in the development of Alzheimer’s disease (AD) and associated cognitive decline is still being investigated. High ubiquity and prevalence in the population have led to a high degree of skepticism about HHV6 as a potential contributor to cognitive decline and dementias. However, recent evidence related to another herpesvirus, herpes simplex virus 1, suggests that reactivation, not carriage, of the virus may be the key factor to explain the dissonance between the virus’ ubiquity and contributions to dementias. With that in mind, we set out to assess cases from the Sanders-Brown Center on …

Uncovering The Role Of Apoe4 On Alzheimer’S Disease-Related Neuroinflammation, Courtney Marie Kloske

Theses and Dissertations--Physiology

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by two hallmark pathologies: amyloid-beta plaques (Ab plaques) and hyperphosphorylated, aggregated tau tangles. These pathologies are typically accompanied by the presence of neuroinflammation which is primarily mediated by microglia. Interestingly, several genetic risk factors that increase the risk of AD also have direct impacts on neuroinflammation. Of interest, Apolipoprotein E (ApoE) is the largest genetic risk factor for AD. ApoE has three isoforms- E4 confers an increased risk for AD, E3 is considered the “control” phenotype, and E2 is protective against AD. E4 plays a role in virtually …

Regulation Of Skeletal Muscle Plasticity By The Gut Microbiome, Taylor R. Valentino

Theses and Dissertations--Physiology

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight …

Novel Mammalian Models For Understanding And Treating Spinal Cord Injury, Michael B. Orr

Theses and Dissertations--Physiology

Spinal cord injury (SCI) is devastating and often leaves the injured individual with persistent dysfunction. The injury persists because humans have poor wound repair and there are no pharmacologic treatments to induce wound repair after SCI. The continued efforts to discover therapeutic targets and develop treatments heavily relies on animal models. The purpose of this project is to develop and study novel mammalian models of SCI to provide insights for the development and effective implementation of SCI therapies.

Lab mice (Mus musculus) are a powerful tool for recapitulating the progression and persistent damage evident in human SCI, but …

Ceramide-Enriched Extracellular Vesicles: A Role In Enhancing Amyloid-Beta Neurotoxicity And Mitochondrial Damage In Alzheimer’S Disease, Ahmed Elsherbini

Theses and Dissertations--Physiology

Alzheimer’s disease (AD) is an age-dependent, progressive, neurodegenerative disorder that is characterized clinically by the impairment of cognitive functions concomitant with behavioral and personality changes. AD is associated with distinct pathological hallmarks, namely, intracellular neurofibrillary tangles comprised of hyperphosphorylated tau protein, extracellular amyloid beta (Aβ) plaques, and marked brain atrophy. Besides their main role as the core component of amyloid plaques, oligomeric Aβ have been shown to be neurotoxic. The exact mechanism of Aβ neurotoxicity is yet to be elucidated.

Recently, a pathogenic function of small extracellular vesicles- also known as exosomes- has been proposed, suggesting that exosomes can transfer …

Apoe As A Metabolic Regulator In Humans, Mice, And Astrocytes, Brandon C. Farmer

Theses and Dissertations--Physiology

Altered metabolic pathways appear to play central roles in the pathophysiology of late-onset Alzheimer’s disease (AD). Carrier status of the E4 allele of the APOE gene is the strongest genetic risk factor for late-onset AD, and increasing evidence suggests that E4 carriers may be at an increased risk for neurodegeneration based on inherent metabolic impairments. A new appreciation is forming for the role of APOE in cerebral metabolism, and how nutritional factors may impact this role. In chapter 1, the literature on nutritional interventions in E4 carriers aimed at mitigating disease risk is reviewed. Studies investigating the mechanism by which …

Targeting Maladaptive Plasticity After Spinal Cord Injury To Prevent The Development Of Autonomic Dysreflexia, Khalid C. Eldahan

Theses and Dissertations--Physiology

Vital autonomic and cardiovascular functions are susceptible to dysfunction after spinal cord injury (SCI), with cardiovascular dysregulation contributing to morbidity and mortality in the SCI population. Autonomic dysreflexia (AD) is a condition that develops after injury to the sixth thoracic spinal segment or higher and is characterized by potentially dangerous and volatile surges in arterial pressure often accompanied with irregular heart rate, headache, sweating, flushing of the skin, and nasal congestion. These symptoms occur in response to abnormal outflow of sympathetic activity from the decentralized spinal cord typically triggered by noxious, yet unperceived nociceptive stimulation beneath the level of lesion. …

Insulin-Like Growth Factor-1 Overexpression Mediates Hippocampal Remodeling And Plasticity Following Tbi, Erica Latrice Littlejohn

Theses and Dissertations--Physiology

Every year over 2.5 million traumatic brain injuries (TBI) occur and are the leading cause of death and disability among adolescents. There are no approved treatments for TBI. Survivors suffer from persistent cognitive impairment due to posttraumatic tissue damage and disruption of neural networks which significantly detract from their quality of life. Posttraumatic cognitive impairment depends in part on the brain's limited ability to repair or replace damaged cells. Immature neurons in the hippocampus dentate gyrus, a brain region required for learning and memory, are particularly vulnerable to TBI. Insulin-like growth factor-1 (IGF1) is a potential therapeutic for TBI because …

The Mechanical Properties Of Non-Failing And Failing Human Myocardium, Cheavar A. Blair

Theses and Dissertations--Physiology

Heart failure is a clinical syndrome that manifests when there are structural and functional impairments to the heart that reduces the ability of the ventricles to fill or eject blood. The syndrome affects ~6 million Americans and is responsible for nearly 300,000 deaths annually. At the core of the syndrome are dysfunctional sarcomeres, the machinery that drives cardiac contraction and relaxation. By assessing the mechanical properties of human cardiac tissue, the information provided in this dissertation will provide data that demonstrates how sarcomeric dysfunction contributes to heart failure in the left and right ventricles. Additionally, these data will supply information …

The Effects Of Perinatal Oxycodone Exposure On The Stress Axis And Neurobehavior, Thitinart Sithisarn

Theses and Dissertations--Physiology

Opiate addiction is now a major public health problem. Pregnant women continue to use opiates during gestation; up to 5.4% of pregnant women report using illicit drugs during pregnancy. Previous studies have shown that perinatal insults and exposure to opiates such as morphine in utero can affect the development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring and are associated with higher risk of developing neurobehavioral problems. Oxycodone, a semisynthetic putative kappa opioid receptor and partial mu opioid receptor agonist is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how …

Ppap2b Expression Limits Lesion Formation In Murine Models Of Atherosclerosis, Paul A. Mueller

Theses and Dissertations--Physiology

Coronary artery disease (CAD) is the leading cause of death in both men and women worldwide and is defined as a narrowing of the coronary arteries due to accumulation of atherosclerotic plaques. Genome-wide association studies have identified risk loci within the gene PPAP2B that confers increased risk of developing CAD. Evidence suggests these aforementioned SNPs are regulating PPAP2B expression in a cis-manner through the interruption of transcription factor binding sites. PPAP2B encodes the lipid phosphate phosphatase 3 enzyme that plays a key role in degrading bioactive lysophosphatidic acid (LPA). LPA has a plethora of effects on vascular tissue and is …

Development And Application Of Gadolinium Free Cardiac Magnetic Resonance Fibrosis Imaging For Multiscale Study Of Heart Failure In Patients With End Stage Renal Disease, Tori A. Stromp

Theses and Dissertations--Physiology

Cardiac magnetic resonance (CMR) is a powerful tool to noninvasively image ventricular fibrosis. Late gadolinium enhancement (LGE) CMR identifies focal and, with T1 mapping, diffuse fibrosis. Despite prevalent cardiac fibrosis and heart failure, patients with end stage renal disease (ESRD) are excluded from LGE. Absence of a suitable diagnostic has limited the understanding of heart failure and obstructed development of therapies in the setting of ESRD. A quantitative, gadolinium free fibrosis detection method could overcome this critical barrier, propelling the advancement of diagnostic, monitoring, and therapy options. This project describes the development of a gadolinium free CMR technique and application …

Targeting Methylglyoxal And Ppar Gamma To Alleviate Neuropathic Pain Associated With Type 2 Diabetes, Ryan B. Griggs

Theses and Dissertations--Physiology

Neuropathic pain affects up to 50% of the 29 million diabetic patients in the United States. Neuropathic pain in diabetes manifests as a disease of the peripheral and central nervous systems. The prevalence of type 2 diabetes is far greater than type 1 (90%), yet the overwhelming focus on type 1 models this has left the mechanisms of pain in type 2 diabetes largely unknown. Therefore I aimed to improve the current mechanistic understanding of pain associated with type 2 diabetes using two preclinical rodent models: Zucker Diabetic Fatty rats and db/db mice. In addition, I highlight the translational importance …

Transmural Heterogeneity Of Cellular Level Cardiac Contractile Properties In Aging And Heart Failure, Premi Haynes

Theses and Dissertations--Physiology

The left ventricle of the heart relaxes when it fills with blood and contracts to eject blood into circulation to meet the body’s metabolic demands. Dysfunction in either relaxation or contraction of the left ventricle can lead to heart failure. Transmural heterogeneity is thought to contribute to normal ventricular wall motion but it is not well understood how transmural modifications affect the failing left ventricle. The overall hypothesis of this dissertation is that normal left ventricles exhibit transmural heterogeneity in cellular level contractile properties and with aging and heart failure there are region-specific changes in cellular level contractile mechanisms.

Age …

Nmda Receptors In The Dorsal Vagal Complex Of Normal And Diabetic Mice, Eva C. Bach

Theses and Dissertations--Physiology

The dorsal vagal complex (DVC), containing the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus nerve (DMV), plays a pivotal role in autonomic regulation. Afferent fibers from peripheral organs and higher brain centers synapse in the NTS, which integrates these synaptic connections as well as information from systemically circulating hormones and metabolites. The integrated information is relayed to the dorsal motor nucleus of the vagus nerve (DMV), which in turn, projects motor fibers to elicit parasympathetic control of digestive and other viscera. Physiological functions mediated by the DVC are disrupted in diabetic patients and …

Lysophosphatidic Acid Production And Signaling In Platelets, Zachary Bennett Fulkerson

Theses and Dissertations--Physiology

Lysophosphatidic acid (LPA) belongs to a class of extracellular lipid signaling molecules. In the vasculature, LPA may regulate platelet activation and modulate endothelial and smooth muscle cell function. LPA has therefore been proposed as a mediator of cardiovascular disease.

The bulk of circulating LPA is produced from plasma lysophosphatidylcholine (LPC) by autotaxin (ATX), a secreted lysophospholipase D (lysoPLD). Early studies suggest that some of the production of circulating LPA is platelet-dependent. ATX possesses an N-terminal somatomedin B-like domain suggesting the hypothesis that ATX interacts with platelet integrins which may localize ATX to substrate in the membrane and/or alter the catalytic …