Integrative Medical Sciences Research Opportunities
Feng Dong, Ph.D.
Role of CXCR4 in Aortic Stenosis
Previously, we found blunted stromal cell-derived factor-1 (SDF-1): CXCR4 axis in diabetes, and our preliminary results show an increase in chronic cardiac myocyte CXCR4 expression in diabetic murine hearts. Moreover, CXCR4 activation in diabetes produces a profound negative inotropic effect (which may seem counterintuitive, but we think it is a key adaptation in the diabetic heart). Furthermore, our preliminary results demonstrate a significantly increased mortality rate of diabetic (high fat, high sugar [HFHS]) mice null for CXCR4 in cardiac myocytes compared to HFHS diabetic wild-type mice. Recently, with our CXCR4 endothelial cell-specific knockout mice, we found that the deletion of CXCR4 in endothelial cells leads to aortic stenosis. This proposal leverages novel models of loss of CXCR4 function in endothelial cells to investigate the role of CXCR4 in aortic stenosis and define the mechanisms of how CXCR4 knockout could affect cardiac function.
Jessica Ferrell, Ph.D.
TGR5 & Alcohol-Associated Liver Disease
Bile acids are the natural ligand for Takeda G protein-coupled receptor 1 (TGR5), an anti-diabetic and anti-inflammatory receptor expressed in the liver, intestine, and brain. It is also a potential therapeutic target for obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (AALD). Tgr5-/- mice have significantly increased expression of fibroblast growth factor 21 (FGF21) upon administration of alcohol via unknown mechanisms. FGF21 is a growth factor involved in suppression of carbohydrate consumption, including ethanol and sugar. FGF21 was shown to be induced after alcohol consumption in rodents and primates/humans, and administration of FGF21 significantly reduces alcohol consumption. However, it is unknown whether the increased Fgf21 in Tgr5-/- mice affects alcohol consumption or nutrient preference. The aim of this study is to determine the role of TGR5 in FGF21 signaling, and to determine if Tgr5-/- mice have altered preference for ethanol consumption.
Adam Goodwill, Ph.D. – 1
Identifying the Coronary Metabolic Dilator
Owing to the need of the heart to constantly oscillate between contraction and relaxation, the metabolic demands of the heart are amongst the highest of any tissue in mammalian physiology. To meet these demands, cardiac tissues rely almost exclusively on aerobic metabolism. Accordingly, the heart must have mechanisms in place to rapidly increase coronary blood flow (oxygen delivery) in response to increases in myocardial demand. While this need is known, the specific mechanism linking these processes remains undefined. In collaboration with other NEOMED faculty including Dr. William Chilian and Dr. Xinwen Wang, we believe that we have developed an experimental approach to allow for novel insights into metabolically driven coronary dilator responses. Our hypothesis is that any metabolic dilator must be initially secreted by cardiac tissue and that increases in myocardial demand will result in proportional increases in this secreted compound. Using a large animal model, we intend to place custom biocompatible catheters directly into the left ventricular free wall of an anesthetized swine model and vary myocardial demand through alterations in cardiac electrical activity and/or chemical stimulation of contractility. We will collect samples of extracellular fluid at specific and carefully controlled levels of myocardial oxygen consumption. This extracellular fluid will then be submitted for metabolomic analyses (Dr. Wang’s group). It is our belief that these analyses will allow for initial identification of plausible, physiologically relevant metabolic dilators.
Adam Goodwill, Ph.D. – 2
Coronary Hypoxemia is a Sufficient Stimulus for Cardiac Effects of Sodium Glucose Cotransporter Type 2 Inhibitors
Since their initial FDA approval in 2013, sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have become an increasingly prescribed drug category for glycemic control in patients with type 2 diabetes mellitus. Through therapeutically induced glycosuria, SGLT2i have been demonstrated to be well tolerated and efficacious in lowering a long-term measure of glucose regulation. Interestingly, numerous outcome studies have demonstrated unexpected and potent decreases in major adverse cardiac effects (MACE) with SGLT2i therapy independent of effects on glucose levels. Understanding of SGLT2i mediated cardioprotection is confounded by the consistent observation that neither SGLT2 mRNA nor protein are measurable in cardiac tissue. Although myriad molecular mechanisms of cardioprotection have been proposed, no mechanism has received general support. Work from our research group has provided compelling data that SGLT2i can act directly on the heart and these actions specifically only occur when the heart is in a condition of disease/damage. It is our assertion that SGLT2i act through a mechanism that is dependent on factors released during myocardial ischemia. We propose a study design that will allow us to better understand the differential role of ischemia vs hypoxemia and stands to provide a dataset for identification of the molecular mechanisms at play in SGLT2i mediated cardioprotection.
James Hardwick, Ph.D. – 1
Synthetic Lethality of Hepatocellular Carcinoma Mediated by Fasting-Induced CYP4 P450
Cancer is the second leading cause of mortality worldwide and is suspected to be the foremost killer in the coming decades by the World Health Organization. Cancer treatments, including surgery, chemotherapy, and radiotherapy, have achieved considerable therapeutic efficacy, but damage to the normal tissue and the subsequent side effects are inevitable. Accordingly, besides the conventional therapy modalities, it is crucial to identify other assistant treatment methods to enhance the therapeutic efficacy further, reduce side effects, and improve prognosis. To improve chemotherapeutic effectiveness, multiple tumor pathways are targeted by drugs that show synthetic lethality (SL). Synthetic lethality is a novel strategy for anticancer therapies, whereby mutations of two genes will kill a cell, but mutation of a single gene will not. A growing number of recent studies in cancer treatments have suggested that factors in the categories of naturopathic medicine profoundly affect the initiation and treatment outcomes of cancer. Fasting therapy is a naturopathic treatment method used as a valid therapeutic modality for acute and chronic diseases in medicine worldwide. In cancer-bearing models, fasting therapy was reported to be a reproducible and efficient intervention in protecting mammals against tumors and prolonged overall survival. The chemotherapy-protection effects of fasting therapy in reducing chemotherapy side effects and related death were also shown in human clinical trials. There is little knowledge of how synthetic lethal chemotherapeutic drugs and fasting interplay improve drug efficacy and reduce systemic toxicity. We hypothesize that induction of omega fatty oxidation cytochrome P450 gene by fasting and inhibition of peroxisomal acyl-CoA oxidase (ACOX) will increase tumor dicarboxylic acids, causing synthetic lethality.
James Hardwick, Ph.D. – 2
Cytochrome P450 Mediated Eicosanoids Mediate Liver Cirrhosis
Cirrhosis is the outcome of chronic liver disease due to progressive liver injury and fibrosis. Cirrhosis leads to portal hypertension and liver dysfunction, progressing to complications such as ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, cirrhotic cardiomyopathy, sarcopenia, hepatocellular carcinoma, and coagulation disorders. The cause of increased portal hypertension and ascites is believed to be vasoconstriction of the portal vein and vasodilation of the splanchnic arterial system. We have recently found the increased cytochrome P450 4a11 mediated increase in the vasoconstrictive 20-HETE eicosanoid in the progression of non-alcoholic fatty liver disease (NAFLD) in human patients. It is believed that 20-HETE mediates its vasoconstrictive effect by activating the GPR75 receptor in endothelial cells and hepatocytes, leading to vasoconstriction and hepatocyte proliferation respectively. This study aims to determine levels of 20-HETE and 12-HETE in human livers from patients with cirrhosis and hepatocellular cell lines, and whether blocking CYP4A11 production of 20-HETE or 20-HETE activation of the GPR75 receptor inhibits hepatocyte cell proliferation.
Heather O’Leary, Ph.D.
Preservation of Endogenous Low Oxygen Signaling Facilitates Hematopoietic Cell Phenotype, Function, and Clinical Utility
Hematopoietic stem cells (HSC) are derived in the bone marrow (BM), give rise to all lineages of cells of the immune system throughout life, and can be transplanted to reconstitute the immune system. The bone marrow niche provides critical signals for hematopoietic stem and progenitor cell (HSC/HSPC) maintenance, self-renewal, and differentiation. Previous studies identified retaining HSC/HSPC in endogenous low Oxygen (low O2, ∼1-4% O2) retains stem cell number, phenotype, and function, which is blunted when HSC/HSPC are exposed to ambient air (20% O2). Despite this knowledge, most studies are performed in air, leaving endogenous signaling mechanisms unidentified, HSC/HSPC phenotype/function diminished, and transplant efficiency sub-optimal leading to high costs and patient complications. To address these knowledge gaps, we have generated and patented novel equipment (US-11633730-B2 Issued 04/2023 (O’Leary)) to isolate/sort/analyze and transplant HSC/HSPC under endogenous, continuous low O2 conditions. Using this novel technology, we generated the first reference landscape of endogenous low O2 HSC/HSPC phenotype/signaling/function. These studies identified important roles for multiple mechanistic pathways including but not limited to; serine peptidase (Dipeptidylpeptidase-4, DPP4) and cytosolic/mitochondrial Calcium (Ca2+) in the optimal regulation of HSC/HSPC phenotype/function in low O2, during health and disease states, and set the foundation for discovery of additional novel regulatory pathways. Retaining HSC/HSPC in low O2 for optimal clinical utilization is technically challenging and brief exposure to ambient air ablates the low O2 enhancement in numbers, phenotype, and function. Therefore, our goals for this study are to identify, and analyze, the differential regulation of endogenous low O2 pathways to facilitate the pharmacologically mimicking of the low O2 HSC/HSPC signaling, phenotype, and function, in air, enhancing transplant efficiency/utility.
Priya Raman, Ph.D.
Effect of Cytokine Storm on Vascular Smooth Muscle Cell Phenotype under Healthy vs. Diseased Conditions
Recent Covid-19 pandemic has provided evidence for a potential link between Covid-19 infection and future risks of cardiovascular complications. Atherosclerosis is a major player in the development of several cardiovascular complications including myocardial infarction, heart failure and stroke. Elevated serum cytokine levels or systemic ‘cytokine storm’ (CS) is one of the most common clinical manifestations of severely ill hospitalized Covid-19 patients. Clinical studies have suggested that pre-existing risk factors for vascular disease, such as diabetes, obesity, and dyslipidemia, can exacerbate the inflammatory responses of the vasculature to CS prompting atherosclerotic complications. However, the molecular mechanism(s) by which CS may trigger atherosclerosis are unknown. De-differentiation of vascular smooth muscle cells (VSMC) from ‘quiescent’ contractile to ‘synthetic’ proliferative phenotype is a key event for development of atherosclerosis. This project aims to study whether CS conditions may induce VSMC phenotypic transition to a diseased proatherogenic phenotype, and further interrogate whether this effect is more pronounced under diabetic conditions. For these studies, we will utilize murine aortic SMC (MASMC) primary cultures isolated from healthy and diabetic mice. MASMCs will be exposed to different concentrations of CS cocktail in vitro for varying periods of time; VSMC signaling, and differentiation marker expression as a readout of VSMC phenotypic transition will be assessed using immunoblotting and immunocytochemistry.
Liya Yin, Ph.D.
The Regulation of Mouse Coronary Collateral Growth
Ischemic heart disease continues to be a leading cause of death, and ill-health in the United States. The presence of coronary collateral vessels—the naturally occurring vessels that supply flow to an area of the heart to bypass a blocked vessel—confers a significant benefit to patients. The incidence of death decreases. The ability to survive a heart attack is better. And the amount of tissue that dies following a heart attack is less. However, the presence of such collateral vessels occurs in only 10-15% of all patients, so that the vast majority suffer the full consequences of death and ill-health in the event of a blockage in a vessel supplying the heart muscle. Currently, our understanding of coronary collateral growth (also termed coronary arteriogenesis) is based on studies in live animals, in which certain inhibitors are administered to reduce the vascular growth. A limitation of such “loss of function” studies is the cellular “target” of the inhibitor is unknown. The inhibitor could be acting on endothelial cells, smooth muscle cells, cardiac myocytes, inflammatory cells, and/or fibroblasts. Currently there is no way to decipher the cell-based mechanisms of coronary blood vessel growth. Moreover pharmacological inhibitors suffer from the problem on non-specificity. To overcome these deficiencies, we use the transgenic mouse model to interrogate many questions regarding regulation of process of coronary arteriogenesis in normal or diseased model (obesity and diabetes) and which cell types may be involved in this adaptive vascular growth. We hope that these studies will eventually lead to new therapies designed to help patients with ischemic heart disease grow new blood vessels in their hearts.
Yanqiao Zhang, Ph.D.
The Role of Intestinal Hepatocyte Nuclear Factor 4α in Alcoholic Liver Disease
Hepatocyte nuclear factor 4α (HNF4α) plays an important role in glucose and lipid metabolism. So far, the role of intestinal HNF4α in the pathogenesis of alcoholic liver disease (ALD) is unknown. In this project, we plan to use mice lacking intestinal HNF4α to investigate the role of HNF4α in ALD. The mice will be subjected to an NIAAA alcohol diet for 2 weeks. We will investigate whether loss of intestinal HNF4α protects against or aggravates ALD as well as the underlying mechanisms.
CONTACT
Nona Hose
Phone: 330.325.6499
Email: nhose@neomed.edu
These projects are funded by the Office of Research and Sponsored Programs (ORSP).
Student Research Fellowship Program
