Molecular Biology Commons^™

The Effects Of Resistance Exercise Training On Insulin Resistance Development In Female Rodents With Type 1 Diabetes, Mitchell James Sammut

Electronic Thesis and Dissertation Repository

The etiology of insulin resistance (IR) development in type 1 diabetes mellitus (T1DM) remains unclear; however, impaired skeletal muscle metabolism may play a role. While IR development has been established in male T1DM rodents, female rodents have yet to be examined in this context. Resistance exercise training (RT) has been shown to improve IR and is associated with a lower risk of hypoglycemia onset in T1DM compared to aerobic exercise. Additionally, the molecular mechanisms mediating RT-induced improvements in insulin sensitivity remain unclear. Therefore, the purpose of this study was to investigate the effects of RT on IR development in female …

Ankyrin Dependent Mitochondrial Function And Bioenergetics In The Heart, Janani Subramaniam, Janani Subramaniam

Dissertations & Theses (Open Access)

ANK2 mutations in patients are associated with numerous arrhythmias, cardiomyopathies, and other heart defects. In the heart, AnkB, the protein encoded by ANK2, clusters relevant ion channels and cell adhesion molecules in several important domains; however, its role at Mitochondria Associated ER/SR Membranes (MAMs) has yet to be investigated. MAMs are crucial to mitochondrial function and metabolism and are signaling hubs implicated in various cardiac pathologies. Among several functions, these sites mediate the direct transfer of calcium from the ER/SR to the mitochondria to modulate ATP synthesis. Given that mitochondrial function and energy production are paramount to cardiovascular heath, …

A Computational Model Of The Line-1 Retrotransposon Life Cycle And Visualization Of Metabolic Networks In 3-Dimensions., Michael D. Martin

Electronic Theses and Dissertations

Computational modeling of metabolic reactions and cellular systems is evolving as a tool for quantitative prediction of metabolic parameters and reaction pathway analysis. In this work, the basics of computational cell biology are presented as well as a summary of physical processes within the cell, and the algorithmic methods used to find time dependent solutions. Protein-protein and enzyme-substrate interactions are mathematically represented via mass action kinetics to construct sets of linear differential equations that describe reaction rates and formation of protein complexes. Using mass action methods, examples of reaction networks and their solutions are presented within the Virtual Cell simulation …

The Impact Of Nitric Oxide On Dendritic Cell Metabolism, Julia Priscilla Snyder

Graduate College Dissertations and Theses

Dendritic cells (DCs) are sentinel immune cells capable of directly sensing and responding to pathogens. Upon pathogen recognition, DCs undergo a process of activation that allows them to participate in the proinflammatory response at the site of infection and to initiate the adaptive immune response through antigen presentation to T cells. Because activated DCs serve as the critical link between innate and adaptive immunity, modulating DC activation could be a powerful tool in various clinical contexts such as vaccine design. DC activation is accompanied by widespread changes in metabolism including the rapid upregulation of glycolysis, which is sustained in DCs …

Characterization And Modulatory Influence Of Pyruvate Kinase Muscle Isoforms 1 And 2 Within The Murine Pluripotent Continuum, Joshua G. Dierolf

Electronic Thesis and Dissertation Repository

Mouse embryonic stem cells (mESCs) and mouse epiblast stem cells (mEpiSCs) represent opposite ends of a pluripotency continuum, respectively referred to as naïve and primed pluripotent states. A third, recently discovered intermediate state has been described as the ‘formative state’. Metabolism has been traditionally regarded as a by-product of cell fate; however, recent evidence now supports metabolism as promoting stem cell fate. Pyruvate kinase muscle isoforms 1 and 2 (PKM1 and PKM2) catalyze the final, rate limiting step of glycolysis generating adenosine triphosphate (ATP) and pyruvate; however, the precise role(s) of these isozymes in naïve, formative, and primed pluripotency is …

Investigating A Novel Function For Phosphoserine Aminotransferase 1 (Psat1) In Epidermal Growth Factor Receptor (Egfr)-Mediated Lung Tumorigenesis., Rumeysa Biyik-Sit

Electronic Theses and Dissertations

Phosphoserine aminotransferase 1 (PSAT1) catalyzes the second enzymatic step within the serine synthetic pathway (SSP) and its expression is elevated in numerous human cancers, including non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutant NSCLC is characterized by activating mutations within its tyrosine kinase domain and accounts for 17% of lung adenocarcinomas. Although elevated SSP activity has been observed in EGFR-mutant lung cancer cells, the involvement of PSAT1 in EGFR-mediated oncogenesis is still unclear. Here, we explore a putative non-canonical function for PSAT1 using biochemical approaches to elucidate unknown interacting proteins and genomic RNA-seq profiling to identify cellular …

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 …

Novel Insights Into The Critical Role Of Cardiolipin In Cellular Metabolism And Mitochondrial Physiology, Jiajia Ji

Wayne State University Dissertations

Cardiolipin (CL) is the signature phospholipid of mitochondria. CL and its remodeling exert critical roles in biological processes both inside and outside of mitochondria. CL abnormalities have been associated with various mitochondrial disorders and aging. Understanding the role of CL in mitochondrial physiology and cellular metabolism could provide valuable insights into cell biology and human health. Several metabolic alterations have been reported in CL-deficient cells, including accumulated lactate, decreased PDH activity, and decreased TCA cycle function. This dissertation connected these findings by showing abnormal NAD+ metabolism in various models lacking CL. Importantly, it shows that NAD+ supplementation improves mitochondrial function …

The Effects Of Induced Polycystic Ovary Syndrome In Nag-1 Transgenic Mice, Nicholas Werner

All Master's Theses

Polycystic ovary syndrome (PCOS) is the leading cause of infertility among women in the US and the most common endocrine disorder among women. PCOS is characterized by cystic ovaries, hyperandrogenism (heightened levels of male sex hormones), altered menstrual cycles and various metabolic dysfunctions. The metabolic symptoms associated with PCOS are difficult to treat, as they are a result of hormonal imbalances, rather than diet. The human Non-Steroidal Anti-Inflammatory Drug Activated Gene (NAG-1) been shown to prevent diet-induced metabolic disorders and weight gain in mice. We hypothesized that the expression of NAG-1 may also prevent hormonal-induced metabolic disorders. To test this …

Antibiotic Drug Discovery Targeting Bacterial Metabolism, Miranda J. Wallace

Theses and Dissertations (ETD)

Over the last century, the use of antibiotics has enabled many advances in modern medicine, making life as we know it possible. In recent years, however, emerging bacterial resistance to virtually all major antibiotic classes has resulted in a worldwide increase in morbidity, mortality, and financial burden associated with drug resistant infections. The antimicrobial resistance crisis presents an urgent need for new antimicrobials with distinct mechanisms of action from existing drugs. The current pharmaceutical pipeline of new antibiotics is limited due to three obstacles: a lack of understanding of resistance mechanisms, a dearth of novel mechanisms of action among new …

Regulation Of Immune Cell Activation And Functionby The Nbmpp2 Protein Andthe Cd5 Co-Receptor, Claudia Mercedes Freitas

Theses and Dissertations

According to the centers for disease control and prevention (CDC) and the world healthorganization (WHO), heart disease and immune related diseases such as diabetes and cancer areamong the leading causes of death around the world. Thus, the regulation of the function ofimmune cell plays a key role in health and disease. Calcium (Ca2+) ions play a critical role inimmune cell activation, function and in a robust immune response. Defects in Ca2+ signalinginfluences the development of cardiac disease, Alzheimer disease, immune cell metabolism,muscle dysfunction, and cancer. Each immune cell is unique in its activation and function,making it relevant to understand how …

Investigating The Effect Of Rutaecarpine On The Benzo[A]Pyrene-Induced Dna Damage In Vitro, You Li

University of the Pacific Theses and Dissertations

Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl …

Cyclic Adenosine Monophosphate Signaling In Mycobacterium Tuberculosis : New Insights Into A Universal Second Messenger, Richard Mcpherson Johnson

Legacy Theses & Dissertations (2009 - 2024)

Despite being the focus of intense research for many years Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the deadliest bacterial pathogen plaguing mankind today. Humans are the sole host and reservoir for Mtb, and Mtb has coevolved closely with its human host for thousands of years. Mtb currently infects over two billion people worldwide and over 1.5 million people die from TB each year, arguably making Mtb the most successful bacterial pathogen on the planet.

A Genetic Analysis Of Nuclear Functions Of The Lipin Protein In Drosophila Melanogaster, Xeniya Rudolf

Graduate Theses and Dissertations

Lipins are a family of proteins that have critical functions in the control of fat storage and energy homeostasis. Biochemically, lipins have two functions. They provide an enzymatic activity (phosphatidate phosphatase or PAP activity) in the glycerol-3 phosphate pathway that leads to the production of storage fats (triacylglycerols). In addition, they play a role in the regulation of genes in the cell nucleus as transcriptional co-regulators. The PAP activity of lipins has been widely studied in a number of organisms. However, the transcriptional co-regulator function is not as well described in the literature. The transcriptional function of lipins depends on …

Cytosolic Acetyl-Coa Promotes Histone H3 Lysine 27 Acetylation In Arabidopsis, Chen Chen

Electronic Thesis and Dissertation Repository

Acetyl-coenzyme A (acetyl-CoA) serves as a central metabolite in energy metabolism and biosynthesis. High level of acetyl-CoA can fuel the tricarboxylic acid (TCA) cycle to generate energy and store excess energy in fatty acids. Meanwhile, it also provides acetyl groups for protein acetylation, which normally occurs at the lysine or arginine residues. Acetylation regulates protein functions largely due to the change of total charges. Acetylation of histones, for example, can lead to loss of the interaction between histone and DNA, thus relaxing chromatin structure and potentially promoting gene expression. However, whether and how acetyl-CoA regulates plant chromatin remains unexplored. Here, …

The Role Of Crebh In Hepatic Energy Regulation Under Metabolic Stress, Roberto Mendez

Wayne State University Dissertations

Lipid metabolism is tightly regulated by nuclear receptors, transcription factors, and cellular enzymes in response to nutritional, hormonal, and stress signals. Hepatocyte specific, cyclic AMP responsive element-binding protein (CREBH) is a transcription factor that is preferentially expressed in the liver and localized in the endoplasmic reticulum (ER) membrane. CREBH is known to be activated by ER stress, inflammatory stimuli, and metabolic signals to regulate hepatic acute-phase response, lipid metabolism, and glucose metabolism. In my thesis research, I have characterized the roles and mechanisms of CREBH in these functions, as well as the overall phenotype of CrebH-null mice. I demonstrated that …

Strategies For Preventing Age And Neurodegenerative Disease-Associated Mitochondrial Dysfunction, Vedad Delic

USF Tampa Graduate Theses and Dissertations

Mitochondrial dysfunction plays a pivotal role in the development of aging phenotypes and aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). Strategies that restore mitochondrial dysfunction may rescue the deficits of central metabolism in these disorders and improve cell survival. For example, we found that modulating the mTOR signaling pathway in a tissue culture model of aging-induced mitochondrial DNA mutation enhanced mitochondrial function as evidenced by increased oxygen consumption. Our previous melatonin studies also led us to hypothesize that caloric restriction and the hormone melatonin would reverse brain mitochondrial dysfunction in animal …

Exploring The Role Of Intracellular Aminopeptidases In Staphylococcus Aureus Pathogenesis, Devon Nicole Marking

USF Tampa Graduate Theses and Dissertations

Staphylococcus aureus is a remarkably pathogenic bacterium that is widely prevalent among the human population. It is the leading agent of skin and soft tissue infections, and is also responsible for causing an array of severe and life threatening diseases. The invasiveness of the pathogen, coupled with increasing antibiotic resistance seen for S. aureus infections, makes this bacterium a prominent public health concern. The extended pathogenicity of S. aureus is largely due to its repertoire of virulence factors, which are typically characterized by being bound to the cell wall, or secreted into the extracellular environment. Previously, our lab identified a …

Diabetes And Obesity Induce Transcriptomic And Metabolomic Changes Enhancing Pancreatic Cancer Aggressiveness, Guermarie Velázquez Torres

Dissertations & Theses (Open Access)

Pancreatic cancer is one of the most aggressive types of cancer, with poor prognosis that lacks effective diagnostic markers and therapies. It is expected that in 2014 the incidence and the mortality of pancreatic cancer in the United States will be 46,420 and 39,590 respectively. Diabetes and obesity are modifiable risk factors associated with accelerated pancreatic carcinogenesis and tumor progression, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that obesity and diabetes mellitus type 2 (DM2) accelerate pancreatic cancer and …

Crosstalk Between Vitamin D₃- And Testosterone-Mediated Signaling In Prostate Cancer Cells, Wei-Lin Winnie Wang

Legacy Theses & Dissertations (2009 - 2024)

Contrary to the common belief that prostate cancer is a hormone dependent disease, the incidence of prostate cancer and associated mortality actually increases significantly after serum androgen levels decline. This led us to hypothesize that androgen depletion in elder men is an underlying cause for the development and progression of prostate cancer. In addition, serum vitamin D₃ levels also decline in older men. Epidemiological and experimental data support an anti-neoplastic activity of vitamin D₃ in colorectal and breast cancers through regulation of cell proliferation, apoptosis, cell differentiation and metastasis. The effects of vitamin D₃ on prostate cancer …

Effects Of Phytochemicals From Rhodiola Crenulata On Highly Invasive Breast Cancer Cell Lines And Embryonic Models Of Migration, Adaris Rodriguez-Cortes

Open Access Dissertations

The root of the Tibetan plant Rhodiola crenulata is part of eastern traditional medicine. Studies have suggested that members of the Rhodiola genus display anticancer properties. In this study we examine the effect of R. crenulata in a cellular model of invasive breast cancer, this disease being the second cause of cancer death among women in the US. Deregulation of the Wnt/β-catenin pathway has been frequently observed in breast cancers and appears to have a key role in the transformation of benign cells to a malignant form. Although mutations of the Wnt growth factor are rarely observed in cancer, the …

Role Of Retinoids In The Regulation Of Hepatic Glucose And Lipid Metabolism, Rui Li

Doctoral Dissertations

The liver plays an important role in controlling glucose and lipid homeostasis. Metabolic abnormalities such as obesity and type 2 diabetes are often associated with profound changes in the expression of genes involved in hepatic glucose and lipid metabolism. Dietary nutrients provide us with macronutrients for energy and micronutrients for maintenance of general health. However, the effects of individual micronutrients on the development of metabolic diseases are unknown. Sterol regulatory element binding protein-1c (SREBP-1c) is the master regulator of fatty acid synthesis, and glucokinase (GK) is the key enzyme in glucose metabolism. Based on the preliminary results from our laboratory …

Identification And Functional Characterization Of The Zebrafish Gene Quetschkommode (Que), Timo Friedrich

Open Access Dissertations

Locomotion in vertebrates depends on proper formation and maintenance of neuronal networks in the hind-brain and spinal cord. Malformation or loss of factors required for proper maintenance of these networks can lead to severe neurodegenerative diseases limiting or preventing locomotion. A powerful tool to investigate the genetic and cellular requirements for development and/or maintenance of these networks is a collection of zebrafish mutants with defects in motility. The zebrafish mutant quetschkommode (que) harbors a previously unknown gene defect leading to abnormal locomotor behavior. Here I show that the que mutants display a seizure-like behavior starting around four days post fertilization …

Regulation Of Protein Degradation In The Heart By Amp-Activated Protein Kinase, Kedryn K. Baskin, Kedryn K. Baskin

Dissertations & Theses (Open Access)

The degradation of proteins by the ubiquitin proteasome system is essential for cellular homeostasis in the heart. An important regulator of metabolic homeostasis is AMP-activated protein kinase (AMPK). During nutrient deprivation, AMPK is activated and intracellular proteolysis is enhanced through the ubiquitin proteasome system (UPS). Whether AMPK plays a role in protein degradation through the UPS in the heart is not known. Here I present data in support of the hypothesis that AMPK transcriptionally regulates key players in the UPS, which, under extreme conditions can be detrimental to the heart. The ubiquitin ligases MAFbx /Atrogin-1 and MuRF1, key regulators of …

Nmr Analyses Show Tcdd Elicits Differences In Hepatic Metabolism In Female C57bl/6 Mice And Sprague-Dawley Rats, Meghan Katherine Makley

Browse all Theses and Dissertations

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) elicits tissue-, sex-, and species-specific effects. This study compares the hepatic response to an oral dose of TCDD in immature ovariectomized (i.o.) C57BL/6 mice (30 µg/kg) and i.o. Sprague-Dawley rats (10 µg/kg), at 72, 120, and 168 h post-dose. Hepatic lipid extracts were analyzed by ¹³C and ³¹P NMR, and aqueous extracts by ¹H and ³¹P NMR.

Consistent with increased lipid content in mice (p≤0.05), TCDD induced increases in hepatic triacylglycerides (TAG), cholesterol, and fatty acids. Principal component analysis of ¹³C spectra show treatment groups separate in mice, but not rats. …