Medicine and Health Sciences Commons^™

Characterization Of Adiposity And Inflammation Genetic Pleiotropy Underlying Cardiovascular Risk Factors In Hispanics., Mohammad Yaser (Anwar)

Electronic Theses and Dissertations

The observed overlap between genetic variants associated with both adiposity and inflammatory markers suggests that changes in both adiposity and inflammation could be partially mediated by common pathways. The pervasive but sparsely characterized “pleiotropic” genetic variants associated with both adiposity and inflammation have been hypothesized to provide insight into the shared biology. This study explored and characterized the genetic pleiotropy underpinning adiposity and inflammation using genetic and phenotypic observations from the Cameron County Hispanic Cohort (CCHC). A total of 3,313 samples and >9 million single nucleotide polymorphisms (SNPs) were examined in this study. Mixed model genome-wide association studies (GWAS) were …

Chronic Effects Of Methylphenidate On Neuronal Viability And Plasticity, Hannah Oakes

Electronic Theses and Dissertations

Methylphenidate (MPH) is the most commonly prescribed drug to treat Attention Deficit Hyperactivity Disorder (ADHD). ADHD is now considered a life-long disorder; therefore, patients take MPH from adolescence into adulthood, highlighting the need for research studying chronic MPH use. MPH increases dopamine and norepinephrine within the synaptic cleft; therefore, chronic use of MPH may lead to changes within important dopaminergic pathways. One pathway, the mesolimbic pathway, includes the hippocampus, an area where adult neurogenesis occurs. We investigated the effects of chronic low and high doses of MPH on neurogenesis and examined levels of a few key proteins linked to cell …

Beyond The Brain: A Study Of Α-Synuclein's Role In Bone And Adipose Tissue, Carolina A. Figueroa

Electronic Theses and Dissertations

α-Synuclein is a polypeptide encoded by the Snca gene, highly expressed in neurons, but it is also found in bones and adipose tissue. Co-expression analysis showed that Snca regulates skeletal homeostasis, and its deletion reduced estrogen deficiency-induced bone loss and weight gain. It is a major component of Lewy bodies (LB) in Parkinson’s disease (PD), leading to progressive immobilization and a range of nonmotor symptoms, including osteopenia, body composition alterations and insulin resistance. This thesis aimed to determine α-Synuclein’s intrinsic role in bone and adipose homeostasis. We discussed the PD pathophysiology emphasizing aspects of bone health and metabolism. By using …

Development, Expansion And Role Of Myeloid-Derived Suppressor Cells In Post-Sepsis Immune Suppression, Tuqa Alkhateeb

Electronic Theses and Dissertations

Myeloid-derived suppressor cells (MDSCs) numbers increase significantly in sepsis and are associated with high mortality rates. These myeloid cell precursors promote immunosuppression, especially in the late (post sepsis) stage. However, the mechanisms that underlie MDSC expansion and programming are not completely understood. To investigate these mechanisms, we used a cecal-ligation and puncture (CLP) mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive phase. Previous studies in our laboratory showed that microRNA (miR)-21 and miR-181b elevate levels of the transcription factor nuclear factor 1 (NFI-A) that promotes MDSC expansion. We report here that miR-21 …

Tissue-Resident Myeloid-Derived Suppressor Cells Modulate Immune Homeostasis In Healthy Adipose., Katlin Brooke Stivers

Electronic Theses and Dissertations

Our goal with this study was to gain insight into the homeostatic immune cell network in healthy adipose tissue. Specifically, we sought to determine if the immature myeloid cells found in healthy and inflamed adipose were, in fact, tissue-resident myeloid-derived suppressor cells (MDSCs). Using various in vitro and in vivo methods, we have uncovered a population of CD11b^Hi Ly6C^Hi Ly6G^- MDSCs resident in healthy adipose tissue. To the best of our knowledge this is the first time that these cells have been investigated and described in healthy adipose tissue. Systemic MDSC depletion lead to the accumulation of …

Mechanisms Of Chromate-Induced Suppression Of Rad51: A One Environmental Health Approach., Rachel M. Speer

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer death. Lung cancer is commonly associated with smoking, however, 1 in 5 women and 1 in 12 men who develop lung cancer are never-smokers. Environmental exposures, therefore, account for a significant portion of lung cancer cases. Hexavalent chromium [Cr(VI)] is a global environmental contaminant and known human lung carcinogen. Cr(VI) and other carcinogenic metals induce chromosome instability, an early event in lung cancer. Structural chromosome instability arises in part due to failed DNA repair. Particulate Cr(VI), the most potent form of Cr(VI), induces DNA double strand breaks and inhibits the high-fidelity DNA …

N-Acetyltranserase 2 (Nat2) Genotype Polymorphism In Cryopreserved Human Hepatocytes And Chinese Hamster Ovary (Cho) Cells., Mariam Refaat Zaky Habil

Electronic Theses and Dissertations

Arylamine N-acetyltransferases, NAT1 and NAT2, catalyze the detoxification and/or activation of drugs and aromatic amine carcinogens. Single nucleotide polymorphisms or SNPs result in different human NAT2 genotypes thus dividing the population into rapid, intermediate, and slow acetylators. We hypothesize allelic variants of NAT2 genotype will decrease levels of N-acetylation, cytotoxicity, oxidative stress, DNA adduct formation, and mutagenesis compared to the reference allele NAT2*4. Cryopreserved human hepatocytes expressing different NAT2 genotypes and NER-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and human NAT2*4, NAT2*5B or NAT2*7B have been used to investigate N-acetylation of different xenobiotics. In …

Soluble Epoxide Hydrolase Inhibition: A Novel Therapeutic Strategy In Alcoholic Liver Disease., Jeffrey Barr Warner

Electronic Theses and Dissertations

Emerging evidence suggests that soluble epoxide hydrolase (sEH) inhibition is a valuable therapeutic strategy for the treatment of numerous diseases. sEH rapidly degrades cytochrome P450-produced epoxygenated lipids (epoxy-fatty acids, epFAs), which generally exert beneficial effects on several cellular processes. sEH hydrolysis of epoxy-fatty acids produces dihydroxy-fatty acids which are typically less biologically active than their parent epoxide. sEH inhibition has shown efficacy in treating numerous pathologies associated with non-alcoholic liver disease, yet no efforts to date have tested the efficacy of sEH inhibition in alcoholic liver disease (ALD). Herein, we measured the levels of sEH expression and epFAs in human …

Tumor-Derived Exosomes Drive Immunosuppressive Macrophages In A Pre-Metastatic Niche Through Nf-Kβ Dependent Glycolytic Metabolic Reprogramming., Samantha M. Morrissey

Electronic Theses and Dissertations

The formation of a pre-metastatic niche is a fundamental requirement for primary tumor metastasis. One of the defining characteristics of a pre-metastatic niche is infiltration of immunosuppressive macrophages. However, how these macrophages acquire their immunosuppressive phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDE) polarize macrophages towards an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent metabolic reprogramming in mice and humans. While NF-κB has previously been shown to act as a direct transcription factor for PD-L1, we report a novel mechanism where TDE-induced NF-κB activation drives PD-L1 expression by augmenting the glycolytic capacity of macrophages through …

Plasmodium Impairs Antibacterial Innate Immunity To Systemic Infections In Part Through Hemozoin-Bound Bioactive Molecules., Christopher Lynn Harding

Electronic Theses and Dissertations

Despite efforts to decrease the global health burden of malaria, infections with Plasmodium species continue to cause over 200 million episodes of malaria each year which resulted in 405,000 deaths in 2018 [1]. One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through activities of heme oxygenase I (HO-I) )-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during …

Bdnf-Related Gene Expression Of Laser Capture Microdissected Glutamate Neurons From The Anterior Cingulate Cortex In Mouse Models Of Autism Spectrum Disorder, Misty Owens

Electronic Theses and Dissertations

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting social behaviors. ASD affects 1 in 59 children with males affected more frequently. ASD is postulated to result from excitatory and inhibitory neurotransmission imbalances. Brain-derived neurotrophic factor (BDNF) signaling affects ASD by influencing synaptogenesis, plasticity, and survival. Studying early in-utero neuropathological changes within ASD requires the use of animal models. Expression of BDNF-associated genes were analyzed within laser capture microdissected pyramidal neurons from the anterior cingulate cortex of male and female BTBR and valproic acid mouse models. No expression differences were found in any gene comparing the three groups. Gender comparisons …

Discovery Of Distinct Mechanisms Underlying The Relationship Between Drug Taking And Predisposing Behaviors, Tyler A. Roy

Electronic Theses and Dissertations

Drug addiction is a heritable disease characterized by compulsive drug use. The biological mechanisms driving addiction remain largely unknown.¹ Previous studies show shared genetic mechanisms underlying addiction risk phenotypes such as anxiety, depression, and novelty/sensation seeking.^2,3 Therefore, high-throughput behavioral screening of these traits in single gene knockout mice can allow for the rapid detection of addiction risk candidate genes and mechanisms. Many of these traits are represented in the Knock-Out Mouse Program (KOMP) phenotyping pipeline. Of the initial two hundred twenty-one strains screened in this program, we tested nineteen phenodeviant knock-out mouse strains with C57BL/6NJ controls (N = …

Behavioral And Neurobiological Evidence Of Epigenetic Transmission In The Neonatal Quinpirole Rodent Model Of Schizophrenia, Wesley Gill

Electronic Theses and Dissertations

Quinpirole is a dopamine D2 receptor agonist that if administered to rats from postnatal day (P)1-21 results in increased dopamine D2 receptor sensitivity throughout the animal’s lifetime. This increase in receptor sensitivity is consistent with schizophrenia. This model has additional consistencies with human schizophrenia, including sensorimotor gating deficits, enhanced behavioral and neurobiological responses to nicotine, and protein alterations consistent with the disorder. In this study, a second generation of the neonatal quinpirole (NQ) rodent model was created to investigate if long term changes caused by NQ treatment would be passed to offspring. NQ treated rats were mated and their offspring …

Transient Display Of Chimeric Proteins On Biological Surfaces As An Effective Strategy For Modulations Of Innate And Adaptive Immune Responses., Pradeep Shrestha

Electronic Theses and Dissertations

The major premise of this dissertation was to transiently display novel immunological ligands on biological membranes as a localized means of modulating innate and adaptive immune responses with applications to bone marrow and pancreatic islet transplantation. In Chapter two, we engineered donor allogeneic bone marrow cells to transiently display a novel form of FasL, SA-FasL, to efficiently purge out alloreactive donor T cells to prevent acute GVHD. In Chapter three, we engineered pancreatic islets with a novel form of CD47, SA-CD47, to modulate instant blood mediated inflammatory reaction (IBMIR) to prevent immediate islet graft loss following intraportal transplantation. GVHD is …

A Protocol Driven Stroke Code's Impact On Door-To-Needle Times, Jesse Osborne

Electronic Theses and Dissertations

Tissue plasminogen activator (tPA) is most effective the faster it is able to be administered to a patient that has been affected by stroke. A Stroke Code is a strategy that acute care facilities implement to reduce the time from diagnosing a stroke to administering tPA. The purpose of this study was to determine if the initiation of a Stroke Code in an acute care hospital reduces the door-to-needle time for patients affected by a stroke. In particular, does a Stroke Code reduce door-to-needle times. The research was conducted using data from April 1, 2014 to December 31, 2014 (pre-Stroke …

The Effect Of Intermittent Cooling On Simulated Basketball Game Performance, Dalton E. Cousin

Electronic Theses and Dissertations

Context: Hyperthermia is induced during prolonged exercise which promotes fatigue and a decline in performance. Basketball athletes have trouble preventing an onset of hyperthermia; thus, cryotherapy is applied intermittently to combat the negative effects.

Objective: To determine, (1) effect intermittent cooling has on simulated basketball performance, perceived exertion and perceived recovery; and (2) change in performance while applying two different forms of intermittent cooling during the Basketball Specific Fatigue Protocol (BSFP).

Design: Crossover study design.

Setting: Indoor collegiate basketball court.

Patients or Other Participants: Sixteen competitively trained recreational basketball athletes (15 males, 1 female; age = 21.1 ± 1.2 yr). …