Medical Physiology Commons^™

Contribution Of Metabolic Cell Swelling On Microcirculatory Perfusion In Septic Shock, Charles E. Payne

Theses and Dissertations

Sepsis, a systemic immunological response that leads to organ-dysfunction, the development of septic shock, and death has mortality rate of 15-25%. A subset of sepsis, septic shock, has an in-hospital mortality rate of 30-50%. Sepsis and its treatment are the most expensive healthcare problem in the United States with the US Agency for Healthcare Research and Quality estimating annual costs over $20 billion. Hypoxia experienced in septic shock induces metabolic cell and tissue swelling leading to further microcirculatory dysfunction and poor tissue perfusion. Reversing metabolic cell swelling corrects these perfusion defects. Two models were used in rats to induce septic …

An Identification Of Tgf-B'S Role In Ischemic Cholangiopathy, Courtney Chmielewski

Theses and Dissertations

Organ transplants are a necessary intervention for many diseases that result in end stage organ failure. The donation pool cannot match the demands of the transplant list, so expanding the pool to include donation after cardiac death (DCD) is desired. However, there are increased odds of graft failure and ischemic cholangiopathy leading to inferior outcomes when DCD livers are used. Ischemic cholangiopathy consists of multiple diffuse strictures and fibrosis of the bile ducts leading to a loss of epithelialization and fibrosis. The cellular mechanism is proposed to be epithelial-to-mesenchymal transition (EMT). TGF-�� is seen as a key initiator of EMT, …

The Effects Of An Inflammasome Inhibitor Olt1177 On The Development Of Ischemic Heart Failure, Joseph S. Aliaga

Theses and Dissertations

Thesis Abstract

THE EFFECTS OF AN INFLAMMASOME INHIBITOR OLT1177 ON THE DEVELOPMENT OF ISCHEMIC HEART FAILURE

By Joseph S. Aliaga, BS

A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University.

Virginia Commonwealth University, 2020

Background: Evidence suggests that prolonged and enhanced pro-inflammatory signaling, modulated by the NLRP3 inflammasome, plays a crucial role in the pathophysiology of several different types of cardiovascular diseases such as acute myocardial infarction (AMI), adverse ventricular remodeling, and heart failure (HF). Consequently, we hypothesize that attenuating the enhanced inflammatory response using a pharmacological NLRP3 …

Pharmacodynamics Of Monoamine Transporter Releasing Agents And Reuptake Inhibitors, Alexa Holloway

Theses and Dissertations

Ligands of the human monoamine transporters encompass a wide range of both illicit and therapeutic drugs that act upon neural circuitry related to reward, motivation, and the processing of salient stimuli. The present study utilizes two methods for analyzing transporter substrates and inhibitors in order to characterize activity and assess potency. The first measures transient changes in intracellular calcium as a surrogate for transporter activity by harnessing the electrical coupling of monoamine transporters and L-type calcium channels. This is used to analyze novel chimera of the strong hDAT inhibitors methylphenidate and ��-PPP in order to assess the contribution of specific …

Novel Orally Active Hydrogen Sulfide-Releasing Compound, Sg1002, Improves Left Ventricular Function And Survival In A Murine Model Of Ischemic Cardiomyopathy, Bharat Balan

Theses and Dissertations

Hydrogen sulfide (H₂S) is a gasotransmitter that has shown cardioprotective effects in the setting of myocardial injury such as acute myocardial infarction (MI) and pressure overload-induced heart failure. However, there are shortcomings in precision and control release from the use of traditional formulations of H₂S in the form of inorganic salts. In this thesis, we sought to determine if the novel, orally active, slow-releasing H₂S-compound SG1002 plays a role in attenuating MI-induced left ventricular (LV) dysfunction and adverse remodeling. We also evaluated the effect of SG1002 on changes in ECG parameters such as QT …

Determining The Effect Of Knocking Out Microrna-21 On Subsarcolemmal And Interfibrillar Mitochondria, Madhur Batra

Theses and Dissertations

Type 2 diabetes mellitus is a growing problem across the world and has significant pathological changes associated with it, including diabetic cardiomyopathy, wherein cardiac function is reduced. MicroRNA-21 has been shown to play a role in both the heart and diabetes so it was thought that knocking out miR-21 could have a protective effect on oxidative phosphorylation function in diabetic mice. Subsarcolemmal and interfibrillar mitochondria were isolated from adult male WT, miR-21 KO, db/db, and double knockout mice (db/db and miR-21 KO cross) and evaluated for function. Knocking out miR-21 in diabetic mice showed a restorative effect in Complex I …

Conduction States Of The Human Dopamine Transporter, Krasnodara Cameron

Theses and Dissertations

Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic …

Risperidone And Its Deconstructed Analogs: Functional Effects On The 5ht2ar, Sneha Shah

Theses and Dissertations

G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that sense extracellular signal and activate intracellular signaling pathways. The serotonin 5HT2A receptor (or 2AR) is one of the GPCRs coupled to Gq proteins, activating PLC and hydrolyzing PIP2. This hydrolysis causes a diffusion of bound PIP2 away from the channel binding site resulting in G protein-gated inwardly rectifying K⁺ channel (GIRK) inhibition and a downstream stimulation of Ca²⁺ release from endoplasmic reticulum stores. Previous experiments have demonstrated that the serotonin 5HTA receptor is a target of serotonergic psychedelic drugs, such as LSD, and partially mediates the action of many …

Inhibition Of Mtor Signaling Protects Against Myocardial Reperfusion Injury, Acute Myocardial Infarction, Scott M. Filippone

Theses and Dissertations

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Currently, the best method of treating cardiac ischemia is early reperfusion which, itself, induces myocardial damage. The mTOR complex is a key regulator of cardioprotection against cell stressors. We hypothesized that reperfusion therapy with Rapamycin, a potent mTOR inhibitor, would reduce infarct size in adult mouse hearts. Rapamycin was administered at the onset of reperfusion following 30 min in situ LAD ligation. After 24 hours of reperfusion, myocardial infarct size and apoptosis were significantly reduced in rapamycin-treated mice compared to control. Rapamycin inhibited pro-apoptotic protein Bax and phosphorylation of …

Comparison Of Two Different Sprint Interval Training Work-To-Rest Ratios On Acute Metabolic And Inflammatory Responses, Christopher R. Harnish

Theses and Dissertations

High intensity exercise is believed to yield greater results on health and human performance than moderate intensity exercise. Extensive research indicates that not only do high-intensity interval training (HIT) and sprint interval training (SIT) produce significant improvements in cardiovascular fitness and disease, they may be more effective at improving long-term metabolic function, including insulin sensitivity (Si), by producing more mitochondria. Moreover, compliance rates for HIT and SIT participation are reported to be the same or better than traditional moderate intensity exercise. Because lack of time is often cited as major hindrance to exercise participation, SIT is also seen as a …