Cellular and Molecular Physiology Commons^™

The Impact Of Age/Rage Signaling On Oxidative Stress Under Diabetic Conditions In Cardiac Fibroblasts, Christopher Dorroh

Honors Theses

Diabetes is a major health concern in the United States, with 1.5 million new cases diagnosed each year. Patients who suffer from diabetes have an increased risk of developing heart failure, a form of cardiovascular disease. Heart failure has been shown to result from increased left ventricular stiffness, which in turn is caused by increased remodeling of the extracellular matrix (ECM). This increase in ECM remodeling is a result of AGE/RAGE signaling, which occurs at a heightened level in the cardiac fibroblast cells of diabetics. Studies have shown that diabetics have elevated levels of AGEs (Advanced Glycation End-Products), which bind …

Glucose Metabolism Of Breast Cancer Sub-Clones That Preferentially Metastasize To The Lungs And Bone, Anna G. Skubiz

Honors Theses

Malignant breast cancers exhibit preferential metastasis to bone and lung (1). While changes in gene expression in lung-specific (LM) and bone-specific metastasis (BoM) lines derived from the MDA-MB-231 breast cancer line have been identified, few metabolic genes are differentially expressed; thus it is unknown if tissue-specific metabolic reprogramming occurs. Two hallmarks of cancer cells are an altered metabolic phenotype characterized by enhanced conversion of glucose to lactate in spite of adequate oxygen availability for complete mitochondrial oxidation of this substrate (referred to as aerobic glycolysis or the Warburg effect) and a greater dependence on glutamine. These changes in primary tumor …

The Role Of Central Ace2 And Nrf2 In Sympatho-Excitation: Responses To Central Angiotensin Ii, Anyun Ma

Theses & Dissertations

Sympatho-excitation is a key characteristic in cardiovascular diseases such as chronic heart failure (CHF) and primary Hypertension (HTN). Evidence suggests that increased sympathetic tone is closely related to activation of the Renin-Angiotensin-Aldosterone system (RAAS) in the central nervous system. An underlying mechanism for sympatho-excitation is thought to be oxidative stress resulting from Angiotensin II (AngII) type 1 receptor (AT1R) activation. Over the past several decades, pharmacological targeting of components of the RAAS have been used as standard therapy in CHF and HTN. However, additional therapeutic strategies are necessary to control these diseases. Oxidative stress is regulated, in part, by the …

Functional Analysis Of A Critical Glycine (Glycine 12) In Beta-Type Connexins Of Human Skin, Rasheed Bailey

Biology Theses

At least five beta-type connexins are expressed in various layers of the skin (Cx26, Cx30, Cx30.3, Cx31, and Cx32) and all include a glycine residue at position 12. Glycine12 (G12) is located about halfway through the cytoplasmic amino terminus and has been the focus of several studies related to connexin diseases and gap junction channel structure. The importance of this residue is evident in the severity and diversity of diseases associated with amino acid substitutions at G12 including hereditary forms of skin disease, deafness and neuropathy. This study uses bioinformatic analysis in combination with mutational analysis and electrophysiology to better …

Microglia-Neuron Interactions In A Mouse Model Of Low Grade Neuroepithelial Tumors, Veolette Hanna

Honors Scholar Theses

Microglia are the macrophages of the brain and spinal cord, playing an important role in the immune response to disease states of the nervous system. This study conducts an investigation on the activity of microglia in response to low grade neuroepithelial tumors. Using mouse models and microglial markers, a qualitative and quantitative analysis of microglia activation, migration, and invasion within the brain cortex during early stages of tumor development was conducted. It was found that the presence of a low grade neuroepithelial tumor in the cortex of one hemisphere of the brain causes significant microglia activation in comparison to the …

Alternative Polyadenylation Modulates Expression Of Pro-Fibrotic Proteins And Contributes To Lung Fibrosis, Junsuk Ko

Dissertations and Theses (Open Access)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects about 5 to 8 million individuals in the world. Despite the high prevalence, there is currently no cure for IPF, and the cause of this disease is still unclear. Our laboratory and collaborators have shown that nudix hydrolase 21 (NUDT21, which is also known as cleavage factor 25, CFIm25) is a key regulator of alternative polyadenylation (APA). NUDT21 depletion causes 3’UTR shortening via APA leading to enhanced mRNA stability and protein translation. This NUDT21 reduction promotes tumor growth in glioblastoma by enhancing expression of oncogenes. Cancer and IPF share …

Aminoacyl-Trna Synthetases, Miguel Angel Rubio Gomez, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The aminoacyl-tRNA synthetases are an essential and universally distributed family of enzymes that plays a critical role in protein synthesis, pairing tRNAs with their cognate amino acids for decoding mRNAs according to the genetic code. Synthetases help to ensure accurate translation of the genetic code by using both highly accurate cognate substrate recognition and stringent proofreading of noncognate products. While alterations in the quality control mechanisms of synthetases are generally detrimental to cellular viability, recent studies suggest that in some instances such changes facilitate adaption to stress conditions. Beyond their central role in translation, synthetases are also emerging as key …

The Implementation Of Exercise For Chronic Kidney Disease And Dialysis Patients, Syed Ahmad Rizvi

Honors College Theses

While commonly known to be the organ that helps with urine production within the human body, the kidney plays one of the most crucial roles in maintaining homeostasis. When establishing all of the roles the kidney has on keeping humans healthy, there is the question of how does the body cope when a patient is diagnosed with kidney failure. One of the more common treatment options that allows the body to continue to function without a kidney is by beginning a patient on a form of dialysis. However, as with any treatment, there will always be a list of side …

Characterization Of A Split-Nluc Assay For Monitoring Changes In Alpha-Synuclein Solubility In Living Cells, Baolong Truong

Honors Program: Senior Projects (Public)

Alpha-synuclein is the primary constituent of Lewy Bodies, protein aggregates associated with Parkinson’s Disease, Dementia with Lewy Bodies, and Multiple Systems Dystrophy. Given the terminal nature of these synucleinopathies, the need for an assay that can report on alpha-synuclein aggregation levels in living systems is critical. Western blotting represents one potential approach to this problem; however, this technique can often be limited by selectivity of available antibodies and experimental reproducibility. Herein, we describe a novel luminescence-based assay capable of detecting alpha-synuclein solubility in bacterial cells. This platform can report on the influence of disease-relevant mutations and small molecules. Antibodies are …

Expression Profiling And Mutant Analysis Reveal Complex Regulatory Networks Involved In Arabidopsis Response To Biotic, Abiotic And Hormonal Stresses, Arjun Sham Valiyaveettil Shamgopal

Biology Dissertations

Biotic and abiotic stress factors consistently threat during different stages of the plant’s life cycle. A complex network of signaling molecules is required to overcome stresses, which is linked to general physiological and molecular processes. Botrytis cinerea is a necrotrophic fungal pathogen that causes grey mold disease on many crops. Apart from B. cinerea, several biotic, abiotic and hormonal stresses have detrimental effects on plant growth and productivity. The aim of this study is to identify the genetic regulations of individual stress types using comparative microarray analyses, and to find out the role of differentially expressed genes in Arabidopsis- …

Potential Role Of The Large Protein Titin In The Development Of Heart Failure, Mary M. Prickett

Senior Theses

I will be exploring the impact of the large protein Titin on heart failure with a preserved ejection fraction (HFpEF). It was hypothesized that myocardial Titin plays a significant role in the progression of HFpEF through isoform, N2BA and N2B, changes. It was hypothesized that an increase in the quantity of N2B Titin, less compliant, and a decrease in N2BA Titin, more compliant, will be observed as HF progresses, contributing to an increase in passive stiffness involved in heart contraction. I will cover a detailed report on the role of Titin in HFpEF and propose research methods to explore further.

Mixed-Lineage Kinase-3 (Mlk3) Plays A Negative Modulatory Role In Insulin Secretion From The Pancreatic Β-Cell, Tyler Russeth, Vijayalakshmi Thamilselvan, Anjaneyulu Kowluru

Medical Student Research Symposium

Glucose-stimulated insulin secretion (GSIS) from the pancreatic β-cell in response to elevated levels of glucose is controlled by a variety of signals including intracellular calcium and nucleotides such as cAMP, ATP and GTP. These cellular signals are responsible for activation of specific kinases that mediate phosphorylation of key exocytotic proteins that lead to GSIS. In the context of protein kinases, mixed-lineage kinases (MLKs) have been implicated in an assortment of cellular functions, including cell proliferation and apoptosis. However, very little is known on potential regulatory roles of MLKs in islet β-cell function, including GSIS. The goal of this study is …

Targeting Trna-Synthetase Interactions Towards Novel Therapeutic Discovery Against Eukaryotic Pathogens, Paul Kelly, Fatemeh Hadi-Nezhad, Dennis Y. Liu, Travis J. Lawrence, Roger G. Linington, Michael Ibba, David H. Ardell

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, …

Nanoformulation Of The Superoxide Dismutase Mimic, Mntnbuoe-2-Pyp5+, Prevents Its Acute Hypotensive Response, Sarah L. Schlichte, Svetlana Romanova, Kenichi Katsurada, Elizabeth A. Kosmacek, Tatiana K. Bronich, Kaushik K. Patel, Rebecca E. Oberley-Deegan, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Scavenging superoxide (O₂^•-) via overexpression of superoxide dismutase (SOD) or administration of SOD mimics improves outcomes in multiple experimental models of human disease including cardiovascular disease, neurodegeneration, and cancer. While few SOD mimics have transitioned to clinical trials, MnTnBuOE-2-PyP⁵⁺ (BuOE), a manganese porphyrin SOD mimic, is currently in clinical trials as a radioprotector for cancer patients; thus, providing hope for the use of SOD mimics in the clinical setting. However, BuOE transiently alters cardiovascular function including a significant and precipitous decrease in blood pressure. To limit BuOE's acute hypotensive action, we developed a mesoporous silica nanoparticle …

Genetic And Cellular Models For The Study Of Ptk2b And Adam10 In Adaptive Thermogenesis And Metabolism, Jared S. Farrar

Theses and Dissertations

In a cellular model, we demonstrate that the non-receptor protein tyrosine kinase 2 beta (PTK2B) plays a critical role in mouse cultured beige adipocyte differentiation. CRISPR/Cas9-mediated knock-out of Ptk2b results in non-differentiating white adipocytes and differentiated beige adipocytes with significantly reduced thermogenic gene and protein expression, enlarged lipid droplet size, and altered mitochondrial respiration. Together, these data in a cell culture system provide evidence for a role of PTK2B in the differentiation of mouse beige adipocytes.

In the process of developing a new mouse model utilizing the adipocyte selective Adipoq-Cre transgenic mouse, strong genetic linkage between a gene …

Focal Augmentation Of Somatostatin Interneuron Function And Subsequent Circuit Effects In Developmentally Malformed, Epileptogenic Cortex, Nicole Ekanem

Theses and Dissertations

Drug-resistant epilepsy (DRE) is a common clinical sequela of developmental cortical malformations such as polymicrogyria. Unfortunately, much remains unknown about the aberrant GABA-mediated circuit alterations that underlie DRE's onset and persistence in this context. To address this knowledge gap, we utilized the transcranial freeze lesion model in optogenetic mice lines (Somatostatin (SST)-Cre or Parvalbumin (PV)-Cre x floxed channelrhodopsin-2) to dissect features of the SST, PV, and pyramidal neuron microcircuit that are potentially associated with DRE. Investigations took place within developmental microgyria’s known pathological substrate, the adjoined and epileptogenic paramicrogyral region (PMR). As well, microcircuit relationships within the previously unexplored range …

Functional Analysis Of Fam83d And Dupd1 – Two Novel Neruogenic Skeletal Muscle Atrophy-Induced Genes, Lisa Michelle Cooper

UNF Graduate Theses and Dissertations

Fam83d and Dupd1 have been identified as novel genes in skeletal muscle that are upregulated in response to neurogenic atrophy in a mouse model. qPCR analysis reveaed both genes are expressed in skeletal muscle with Fam83d expression being highest during myoblast proliferation, while Dupd1 expression is highest during myotube differentiation. Overexpression of either protein results in inhibition of proper muscle cell differentiation as evidenced by repression of both myosin heavy chain and myogenin expression. Characterization of transcriptional activity revealed both genes are modulated by myogenic regulatory factors and additionally, Dupd1 expression is enhanced by dexamethasone treatment. Assessment of subcellular localization …

Isothermal Environmental Heat Energy Utilization By Transmembrane Electrostatically Localized Protons At The Liquid-Membrane Interface, James Weifu Lee

Chemistry & Biochemistry Faculty Publications

This study employing the latest theory on transmembrane electrostatic proton localization has now, for the first time, consistently elucidated a decades-longstanding bioenergetic conundrum in alkalophilic bacteria and more importantly discovered an entirely new feature: isothermal environmental heat utilization by electrostatically localized protons at the liquid-membrane interface. It was surprisingly revealed that the protonic motive force (equivalent to Gibbs free energy) from the isothermal environmental heat energy utilization through the electrostatically localized protons is not constrained by the overall energetics of the redox-driven proton pump system because of the following: (a) the transmembrane electrostatically localized protons are not free to move …

Divergence In Neuronal Calcium Dysregulation In Brain Aging And Animal Models Of Ad, Adam Ghoweri

Theses and Dissertations--Pharmacology and Nutritional Sciences

Neuronal calcium dysregulation first garnered attention during the mid-1980’s as a key factor in brain aging, which led to the formulation of the Ca²⁺ hypothesis of brain aging and dementia. Indeed, many Ca²⁺-dependent cellular processes that change with age, including an increase in the afterhyperpolarization, a decrease in long-term potentiation, an increased susceptibility to long-term depression, and a reduction in short-term synaptic plasticity, have been identified. It was later determined that increased intracellular Ca²⁺ with age was due to increased Ca²⁺ channel density, elevated release from intracellular Ca²⁺ stores, and decreased Ca²⁺ buffering …

Remodeling In The Actin Core Of The Auditory Hair Cell Stereocilia As A Novel Component Of Temporary Noise-Induced Hearing Loss, Jonathan Michael Grossheim

Theses and Dissertations--Physiology

The rigid, paracrystalline actin core of auditory hair cell stereocilia is extremely stable and after initial formation must persist for the life of the cell to preserve hearing in mammals. In healthy hair cells, turnover of actin molecules occurs only in a small region near the tips of stereocilia, while the actin filaments of the shaft are stable. For decades damage to the actin core of stereocilia from acoustic trauma has only been attributed to cases of permanent noise-induced hearing loss. Here, we show that repairable actin core damage occurs in temporary noise-induced hearing loss from moderate acoustic trauma.

We …