Medical Physiology Commons^™

Nicotinamide Riboside And Beta-Hydroxybutyrate Activate Parallel Pathways For C. Elegans Lifespan Extension, Mckenzie Peters

Undergraduate Honors Theses

Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD⁺) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD⁺ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPR^mt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD⁺ and through increasing levels …

Substrate Stiffness: A Mechanical Determinant Of Endothelial Phenotype, Sunita Subedi Paudel

<strong> Theses and Dissertations </strong>

Endothelial cells (ECs) adhere to their neighboring cells via adherens and tight junctions, and to the basement membrane via focal adhesions. These structural elements are constantly remodeling i.e., even in a quiescent state, cells are in constant motion. ECs sense the stiffness of the basement membrane, and this stiffness is a physiological signal that control the cellular phenotype. Whereas the normotensive pulmonary circulation has a substrate stiffness that is ~1.25-4 kPa, vascular remodeling in pulmonary arterial hypertension (PAH) increases substrate stiffness to ~30 kPa. The impact that this increase in substrate stiffness has no cell size, shape, and speed was …

A Design, Development, And Evaluation Of Bio-Patch For Myocardial Tissue Repair, Yaya Zhang

Theses and Dissertations (ETD)

Introduction. Ischemic heart disease (IHD) is a major concern of human health issue. The structural repair and functional recovery of injured hearts is a major challenge in the clinical setting. Preclinical studies over last 10 years have demonstrated the potential of using stem cells to treat IHD, but the efficacy of this therapy is jeopardized by uncontrollable migration and low survival of the injected stem cells. An approach based on tissue engineering enabling target-specific stem cell delivery such as cardiac patches has emerged as an alternative solution for stem cell therapy for IHD. It employs scaffold materials to engulf various …

The Effect Of Cancer Cachexia Progression On The Feeding Regulation Of Skeletal Muscle Protein Turnover, Brittany R. Franch

Theses and Dissertations (ETD)

Cancer cachexia is defined as the unintentional loss of skeletal muscle mass with or without fat loss that cannot be reversed by conventional nutritional support. Cachexia occurs in ~20% of cancer patients. More specifically, 50% of lung cancer patients, the most common cancer worldwide, develop cachexia. Cachexia occurs most often in lung and gastrointestinal cancers, whereas breast and prostate have the lowest rate of cachexia. Cancer-induced cachexia disrupts skeletal muscle protein turnover (decreasing protein synthesis and increasing protein degradation). Skeletal muscle’s capacity for protein synthesis is highly sensitive to local and systemic stimuli that are controlled by mTORC1 and AMPK …

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 …

Conditional Loss Of Engrailed 1/2 In Rhombic Lip-Derived Neurons Increases Intrinsic Rhythmicity And Decreases Overall Variability Of Eupneic Respiration, Angela P. Taylor

Theses and Dissertations (ETD)

Evidence for a cerebellar role during cardiopulmonary challenges has long been established, but investigation into cerebellar involvement in eupneic breathing has been inconclusive. Given the view of the cerebellum (CRB) as a temporally coordinating structure, any investigation into the CRB during respiration must evaluate rhythm and variability of the respiratory sequence. In this study, we chose an elegant model of cerebellar neuropathology, Atoh1-En1/2 CKO, where mutant animals have conditional loss of the developmental patterning gene Engrailed 1/2 in rhombic lip-lineage neurons and exhibit a proportional scaling-down of neuron number in hypoplastic lobules of the CRB. We utilized whole-body unrestrained plethysmography …

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

Dissertations & 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 …

Effects Of Nicotinamide Riboside And Beta-Hydroxybutyrate On C. Elegans Lifespan, Jeffery Peters

Undergraduate Honors Theses

The nicotinamide riboside (NR) form of vitamin B₃and the ketone body ß-hydroxybutyrate (BHB) are two of the most promising natural compounds yet identified for the treatment of aging and aging-related diseases. Forms of vitamin B₃are precursors for the synthesis of the coenzymes nicotinamide adenine dinucleotide (NAD(H)) and nicotinamide adenine dinucleotide phosphate (NADP(H)). In aged cells levels of NAD⁺decline, decreasing metabolism and decreasing activity of protective sirtuin protein deacetylases. In aged cells NR, but not more common forms of vitamin B3, boost NAD⁺levels. BHB is naturally produced by the body when individuals fast …

The Purification Of Human Adult Progenitor Cell Types To Promote Angiogenesis, Stephen E. Sherman

Electronic Thesis and Dissertation Repository

Cellular transplantation strategies have aimed to combat critical limb ischemia (CLI) by inducing endogenous blood vessel regeneration. Transplantation of mesenchymal stromal cells (MSC) for CLI has proven safe and well-tolerated but demonstrated only modestly improved clinical outcomes explained in part by a lack of MSC survival and/or potency in ischemic tissues. This thesis focuses on the development of improved transplantation strategies for patients with CLI utilizing purified pro-angiogenic subsets of MSC and endothelial colony forming cells (ECFC) seeded within decellularized adipose tissue (DAT) bioscaffolds. First, I investigated whether purification of bone marrow-derived MSC based on a conserved stem cell function, …

Naktide Targeted To Adipocytes Ameliorates Western Diet Induced Obesity, Rebecca D. Pratt

Theses, Dissertations and Capstones

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. It is believed that cellular oxidant stress plays a key role in both the development and maintenance of obesity as well as its associated comorbidities such as diabetes, cardiovascular disease, and nonalcoholic steatohepatitis (NASH). We have previously reported that systemic administration of pNaKtide, which targets the Na/K-ATPase oxidant amplification loop was able to decrease oxidative stress and adiposity in mice fed a high fat and fructose supplemented western diet (WD). As adipocytes are believed to play an active role in the development of obesity and …

Signaling Induced By Inflammatory Mediators In The Rodent Pulmonary Microvasculature, Rachel Escue Helms

Theses and Dissertations (ETD)

Acute lung inflammation (ALI), stemming from a disproportionate and detrimental immune response, may arise from or complicate other disease states, leading to the often-fatal acute respiratory distress syndrome (ARDS). Because of the many culpable factors and differing points of induction, pinning down the signaling mechanisms involved in the morbidity of this disorder as well as defining an effective treatment has proved problematic. However, the most detrimental characteristic of this condition is seen regardless of the development of the response: increased microvascular permeability. Because of the architecture and the size of the pulmonary microvascular network, the lungs have a resident, sequestered …

Protein Trafficking Of Bk Channel Β1 Subunits In Cerebral Artery Myocytes, Xue Zhai

Theses and Dissertations (ETD)

Rationale: Large-conductance calcium (Ca²⁺)-activated potassium channels (BK) are expressed in arterial myocytes to control arterial contractility. It is composed of pore- forming BKα and auxiliary β1 subunits. Auxiliary β1 subunits associate with BKα which modulate Ca²⁺ sensitivity of BK channel. Previous data showed that BKα locates at cell membrane, whereas β1 subunits are primarily intracellular which regulated by Rab11A- positive recycling endosomes. Endothelin-1 (ET-1), a vasoconstrictor, induces contraction of myocytes. ET-1 inhibits BK channel but mechanisms are not fully understood. It is unclear that vasoconstrictors regulate the cellular distribution of BK channels. Furthermore, BK channels are involved …

Characterization Of The Hepatotoxicity Of Rifampicin And Isoniazid, Christopher T. Brewer

Theses and Dissertations (ETD)

In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase of protoporphyrin ix (PPIX), the penultimate heme precursor. Excess PPIX is believed to bind to bile acids, precipitate in bile canaliculi, and form bile plugs leading to cholestasis fol owed by liver injury. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to up-regulate Alas1 but down-regulate Fech protein levels in mice; however the mechanism of isoniazid mediated heme synthesis …

Role Of Occludin In The Regulation Of Epithelial Tight Junctions, Bhargavi Manda

Theses and Dissertations (ETD)

Tight junctions (TJ) constitute the primary component of epithelial barrier function, a disruption of which is involved in the pathogenesis of many gastrointestinal, pulmonary and renal diseases. Occludin is the major transmembrane protein of TJ, a deletion of which leads to a complex phenotype including chronic inflammation in several epithelial tissues of occludin deficient mice and poor TJ integrity in epithelial cell lines. Its down regulation was seen in Crohn’s disease, tumors of the colon, brain, endometrium and breast cancer. Occludin is also known to be a target that enables Hepatitis C Virus infection and bacterial pathogenesis. But the specific …

Mechanism Of Chimeric Vaccine Mediated Immune Suppression Of Human Dendritic Cells, Jacques Christian Mbongue

Loma Linda University Electronic Theses, Dissertations & Projects

Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of …

Regulation Of Uv-Protective Pathways Downstream Of The Melanocortin 1 Receptor In Melanocytes, Erin M. Wolf Horrell

Theses and Dissertations--Physiology

Malignant cutaneous melanoma is the deadliest form of skin cancer, and a majority of melanoma diagnoses are a result of exposure to ultraviolet (UV) radiation. UV radiation causes DNA damage, which if not repaired correctly via nucleotide excision repair (NER) can result in mutations and melanomagenesis. The melanocortin 1 receptor (MC1R) is a G_s protein coupled receptor located on melanocyte plasma membranes and is involved in protecting the skin from UV induced damage. MC1R signaling results in the activation of two protective pathways: 1) induction of eumelanin synthesis downstream of micropthalmia-associated transcription factor (MITF) and 2) acceleration of NER …

Characterization Of The Nicotine-Induced Endoplasmic Reticulum Stress Response In The Rat Placenta In Vivo And In Vitro, Michael Ka Chun Wong

Electronic Thesis and Dissertation Repository

Nicotine exposure during pregnancy leads to adverse health outcomes, including compromised placental development. Although the molecular mechanisms remain elusive, recent studies identified that endoplasmic reticulum (ER) stress may underlie poor placentation. Therefore, we were interested in investigating the effects of nicotine exposure on the ER stress response in the placenta. A well-established maternal nicotine exposure rat model and Rcho-1 trophoblast giant cell model were utilized to address the research questions. Maternal nicotine exposure in vivo led to elevated ER stress in association with impaired disulfide bond formation and hypoxia. Nicotine exposure in vitro further differentiated that ER stress may be …

Inhibition Of Elongation Factor 1a-1 Activity And Hepatic Lipotoxicity, Alexandra Margaret Anne Hetherington

Electronic Thesis and Dissertation Repository

Elongation factor 1A-1 (eEF1A-1) was previously identified as a mediator of fatty acid-induced cell death (lipotoxicity) downstream of endoplasmic reticulum (ER) stress. Furthermore, inhibition of the peptide elongation activity of eEF1A-1 with the cyclic depsipeptide didemnin B (DB) diminishes ER stress and lipotoxicity in cultured hepatocytes. Since ER stress is involved in nonalcoholic fatty liver disease (NAFLD), it was hypothesized that administration of DB to obese mice with NAFLD would reduce hepatic lipotoxicity. Treatment with DB for one week improved several parameters associated with hepatic lipotoxicity and modestly decreased food intake without evidence of illness. Liver triglycerides and protein markers …

Timp3 Regulation Of Macrophage Activation And Apoptosis, Michael S. Brock

Electronic Thesis and Dissertation Repository

Acute respiratory distress syndrome (ARDS) is a lung disease involving profound inflammation. Origins of persistent inflammation in select cases of ARDS are poorly understood, and we propose persistent inflammatory macrophages may be one of its mechanisms. Macrophages polarize to either promote inflammation, or suppress inflammation. Tissue inhibitor of metalloproteinases 3 (TIMP3) reduces the pro-inflammatory polarization in macrophages. Additionally, studies have shown TIMP3 promotes apoptosis, and its absence delays recovery from bleomycin-induced lung injury.

We hypothesize that TIMP3 promotes apoptosis of murine macrophages through inhibition of metalloproteinase activity and stabilization of FAS on the cell surface. Pro-inflammatory Timp3^-/- bone marrow-derived …

Novel Therapeutic Approaches For Ischemic Heart And Brain Injury: Modulation Of Toll-Like Receptor-Mediated Signaling Pathways And Pi3k/Akt Signaling, Chen Lu

Electronic Theses and Dissertations

Innate immune and inflammatory responses contribute to myocardial and cerebral ischemia/reperfusion (I/R) injury. Toll-like receptors (TLRs) play a critical role in the induction of innate immune and inflammatory responses via activation of nuclear factor kappa B (NF-κB). We have shown that activation of NF-κB contributes to myocardial and cerebral I/R injury. Indeed, inhibition of TLR4-mediated NF-κB activation significantly decreased myocardial and cerebral I/R injury via activation of PI3K/Akt signaling. PI3K/Akt signaling is an important pathway in regulating cellular survival and inflammatory responses. Therefore, an important question is how to differentially modulate PI3K/Akt signaling and TLR/NF-κB-mediated signaling pathway during I/R injury? …

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …