Medicine and Health Sciences Commons^™

Metabolic Regulation Of Myocardial Adaptation To Exercise., Andrew Alan Gibb

Electronic Theses and Dissertations

While the benefits of exercise affect several organs, a significant adaptive response occurs within the heart. Exercise promotes cardiac growth, increases angiogenesis, and enhances cardiac function and these adaptations are associated with a cardioprotective phenotype. Additionally, extensive evidence shows that exercise dynamically regulates myocardial metabolism. This can be attributed to both changes in hormonal stimulation, increases in bioenergetic demand, and the bioavailability of circulating substrates. However, it is unclear whether these changes in metabolism contribute to physiologic cardiac growth. We reason that exercise-induced changes in metabolism are required to balance the catabolic and anabolic reactions needed for growth. Specifically, we …

The Role Of Hif-1Α In Intestinal Epithelial Barrier Function In Alcoholic Liver Disease., Tuo Shao

Electronic Theses and Dissertations

Hypoxia inducible factor 1 α (HIF1α) is an oxygen-responsive subunit. HIF-1α plays a pivotal role in many pathophysiological processes. In addition to oxygen availability, HIF-1α can be regulated by multiple other factors in response to various pathophysiological processes. Previous studies showed that hepatic HIF-1α could be beneficial or harmful in experimental alcoholic liver disease (ALD). However, the role of intestinal HIF-1α in ALD has not yet been studied. Given the critical role of the gut-liver axis in ALD, it is important to elucidate the role of intestinal epithelial HIF-1α in ALD. In the first chapter, we used wide type (WT) …

Ubqln1 : A Multi-Domain Protein With Multiple Functions., Zimple Kurlawala

Electronic Theses and Dissertations

There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA) and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders including Alzheimer’s disease, Amyotropic Lateral Sclerosis and lung cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation. UBQLN1 …

Revisiting Neutrophil Responses To Toll-Like Receptor 4 : Influence Of Ligand Structures And Cellular Environments., Shuvasree Sengupta

Electronic Theses and Dissertations

Neutrophils respond to bacterial LPS through Toll-like receptor 4 (TLR4), which activates or potentiates immune defensive functions and prolongs cell survival. Activation of TLR4 signaling in neutrophils is beneficial for effective clearance of LPS-bearing Gram-negative bacteria, but may also drive aberrant inflammation if not stringently regulated. The regulatory processes by which neutrophil functions are calibrated to respond appropriately to different LPS-bearing bacteria are incompletely understood. Described here are investigations that reveal an unexpected sensitivity of TLR4 in neutrophils to small changes in LPS structure typical of various Gram-negative bacteria, including those that are dangerously virulent (Escherichia coli and Salmonella …

Spinal Cord Injury Induced Cardiac Decline And The Limitations Of Exercise., Kathryn Michele Deveau

Electronic Theses and Dissertations

There is a general consensus that the level and the severity of spinal cord injury (SCI) impacts chronic cardiac abnormalities such that high thoracic and cervical SCI are the most severely affected. Furthermore, the extreme degree of immobility/inactivity experienced by the persons with SCI has implications on cardiac decline. Yet it has been difficult to separate the relative contributions of the decentralized autonomic nervous system (ANS) and the immediate and profound inactivity to chronic cardiac abnormalities. As such, this body of work sought to characterize a contusion SCI that results in persistent CV dysfunction. Echocardiography, Dobutamine stress echocardiography and pressure …

The Effects Of Moderate Alcohol Consumption And Inflammation On The Hepatic Matrisome And The Renal Cortex Proteome., Christine E. Dolin

Electronic Theses and Dissertations

Background. The association of chronic ethanol (EtOH) consumption with extracellular matrix (ECM) changes in alcoholic liver disease (ALD) is well established in the context of hepatic fibrosis. However, it is becoming increasingly understood that the hepatic ECM responds dynamically to stress well before fibrosis. The term “transitional tissue remodeling” describes qualitative and quantitative ECM changes in response to injury that do not alter the overall architecture of the organ; these ECM changes may contribute to early disease initiation and/or progression. The nature and magnitude of these changes to the ECM are currently poorly understood. In contrast to the liver, EtOH …

Trunk And Respiratory Motor Control In Typically Developing Children And Its Implications In Children With Chronic Spinal Cord Injury., Goutam Singh

Electronic Theses and Dissertations

Independent sitting is a major milestone and is also a prerequisite for optimal performance of activities of daily living (ADLs). Development of sitting posture control is a dynamic process involving control of degrees of freedom of head and trunk. Traditionally, trunk has been modeled as a single unit (segment). However, recent studies have suggested that it is made up multiple spinal units, controlled by a combination of trunk muscles. During typical development, posture control of trunk is different for different trunk segments. This motor development of trunk control is a complex process due to constant interaction between the nervous system …

Targeting The Glucose Metabolism Of Myeloid-Derived Suppressor Cells (Mdscs) To Stimulate Cancer Immunity., Jaspreet Grewal

Electronic Theses and Dissertations

Myeloid derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells that are significantly increased in cancer patients and correlate with higher stage and poor prognosis. MDSCs negatively modulate anti-tumor immunity, suppress T cell activity, promote angiogenesis and increase the risk of metastasis. In this study, we report that monocytic-MDSCs (M-MDSCs) but polymorphonuclear-MDSCs (PMN-MDSCs) over-express 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases 3 (PFKFB3), an important regulator of glycolysis. Furthermore in the melanoma model, M-MDSCs but not PMN-MDSCs suppressed T cell function which correlated with PFKFB3 over-expression and increased rate of glycolysis. PFKFB3 inhibition with the first-in-class small molecule inhibitor, PFK-158 reversed M-MDSC …

Combating Malignant Melanoma With The Multifaceted Soy-Dervied Peptide Lunasin., Christopher Paul Shidal

Electronic Theses and Dissertations

Lunasin is a 44 amino acid peptide that has been shown to have cancer chemopreventative and chemotherapeutic properties. This study investigated the potential utility of Lunasin as a chemotherapeutic in melanomas. Studies showed that Lunasin had little activity against established melanoma cell lines using adherent culture methods; however, Lunasin’s in vitro activity was significantly higher in non-adherent colony-forming assays and oncosphere formation. These results led to the investigation of whether or not Lunasin has selective effects on cancer initiating cells (CIC) that are known to be present in melanomas. It was revealed that Lunasin selectively inhibited the proliferation of high-ALDH …

Characterization Of A Mutant Oncolytic Adenovirus And The Role Of Jnk In Enhancing Virotherapy., Stephen L. Wechman

Electronic Theses and Dissertations

Oncolytic adenoviruses (Ads) have great therapeutic potential for lung cancer treatment. Cancer selective E1b-deleted Ads are safe; however, their clinical cancer therapeutic efficacy remains limited. The limited efficacy of Ad virotherapy is due to many factors including inefficient cancer cell lysis, Ad release and spread. Progress in overcoming these barriers to Ad virotherapy are hampered by limited knowledge of the genes associated with enhanced Ad release and spread and the dearth of understanding of the mechanisms by which E1b-deleted Ads cause cancer cell lysis. The role of c-JNK n- terminal kinase (JNK) phosphorylation in this process remains unknown. …

The Interaction Of Homoserine Lactones And Paraoxonase 2 Modulates Cell Death Signaling And Cell Proliferation., Aaron Mackallan Neely

Electronic Theses and Dissertations

Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule that functions to facilitate bacteria-bacteria communication. C12 has also been reported to affect many aspects of human host cell physiology, including evoking cell death in various types of cells. However, the signaling pathway(s) leading to C12-triggerred cell death remains unclear. To clarify cell death signaling induced by C12, we examined mouse embryonic fibroblasts (MEFs) deficient in one or more caspases. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in cells, probably through the direct induction of mitochondrial membrane permeabilization. Importantly, C12 induces apoptosis …

The Actin-Severing Protein Cofilin Is Downstream Of Neuregulin Signaling, Is Regulated By The Tumor Suppressor Merlin, And Is Essential For Schwann Cell Myelination, Nicklaus Sparrow

Electronic Theses and Dissertations

Myelination is a complex process requiring coordination of directional motility and an increase in Schwann cell (SC) size to generate a multi-lamellar myelin sheath. Regulation of actin dynamics during myelination is poorly understood. However, it is known that myelin thickness is related to the abundance of neuregulin1-type III (NRG) expressed on the axon surface. NRG binding to ErbB2/3 receptors on the Schwann cell surface initiates signaling cascades necessary for myelination. We identify cofilin1, an actin depolymerizing and severing protein, as a downstream target of NRG-ErbB2/3 signaling in rat SC. A five minute exposure of SCs to NRG triggers phosphorylation of …

The Microbial Ecosystem Of Beer Spoilage And Souring: Competition And Cooperation In The Age Of Bioinformatics, Andrew Kettring

Electronic Theses and Dissertations

The brewing industry generates $350 billion in revenue in the US annually, representing 1.9% of the gross domestic product. Spoilage is a persistent problem throughout production and distribution that causes economic loss, and is therefore meticulously avoided. Contrarily, artisanal sour beers are necessarily produced by a diverse variety of these spoilage organisms metabolically interacting in symbiosis as a microbial ecosystem. We sought to gain insight into factors driving assembly of microbial communities by testing a long-debated Darwinian hypothesis. A collection of community members were screened in co-culture and novel bioinformatics tools were developed to predict observed interactions. A fundamental understanding …

Implication Of Alpha-Synuclein Transcriptional Regulation And Mutagenesis In The Pathogenesis Of Sporadic Parkinson's Disease, Sambuddha Basu

Electronic Theses and Dissertations

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by selective loss of dopaminergic neurons (DA neurons) from the substantia nigra (SN) of the mid-brain. PD is classically associated with cytoplasmic inclusion of aggregated proteins called Lewy bodies. alpha-synuclein (α-SYN) coded by the gene SNCA, is one of the major components of Lewy body and neurite along with several other proteins like ubiquitin, neurofilament to name a few. PD is broadly categorized into two groups based on their incidence of occurrence. First is the familial form that occurs due to known genetic aberrations like mutation, gene duplication/triplication in important PD …

Targeted Therapy Development For Neurofibromatosis Type 2, Marisa Fuse

Electronic Theses and Dissertations

Neurofibromatosis type 2 (NF2) is a debilitating disease characterized by the formation of bilateral vestibular schwannomas, which compress the vestibulocochlear nerve and cause deafness. Additional peripheral schwannomas, meningiomas and ependymomas may also form. NF2 is caused by mutations in the NF2 gene, resulting in the loss of function of the merlin tumor suppressor. Merlin functions in multiple signaling pathways and its absence in Schwann cells yields increased cell survival and proliferation, thereby causing schwannoma formation. First line treatment for NF2 is watchful waiting and surgical removal of tumors, potentially resulting in facial paralysis and deafness. To date, there are no …

The Effect Of Acute Pain On Executive Function, Jenna M. Morogiello

Electronic Theses and Dissertations

Background: Executive functions are high-level cognitive processes that allow a person to successfully engage in an independent and self-fulfilling life. Previous literature indicates that acute pain can affect executive function, which may be due to a limited amount of shared neural resources of the brain.

Objective: The purpose of this study was to determine if acute pain affects executive function in recreationally active individuals who sustain a musculoskeletal injury.

Methodology: Twenty-four participants who presented with acute pain due to a musculoskeletal injury underwent a neuropsychological battery within 72 hours of injury and within two weeks from the initial testing session. …

The Reliability Of The Navicular Drop Test And Its Transferability To Dynamic Movement, Joshua Krispin

Electronic Theses and Dissertations

Background: Navicular drop can be defined as the distance the navicular tuberosity moves from a standing weight bearing to a standing neutral position, as the subtalar joint moves from a relaxed position to a neutral position. Navicular drop is an important measurement for clinicians used to describe foot function, pronation, and excessive movement seen in several pathologies. Objective: The purpose of this study is to see if navicular drop is influenced by mode or speed of locomotion, if it is will there be other influences such as the forefoot and heel soft tissue, and will those factors influence those measures. …