Integrative Medical Sciences Research Opportunities
Yeong-Renn Chen, Ph.D.
Roles of Mitochondrial HCCS in the Regulation of Healthspan by Enhancing Cardiac Resilience to Heart Failure
The objective of this proposed research project is to study the role of mitochondrial health in cardiac adaptation to pathological conditions of chronic ischemia and reperfusion in controlling the disease development of heart failure. The focus of this project will be on one disease model of heart failure caused by chronic myocardial infarction in the aging process, one major upstream biosynthetic enzyme, cytochrome c heme lyase (HCCS) in the cardiac mitochondria, and cardiac resilience to ischemia and reperfusion injury during aging process. The mitochondrial HCCS as the major upstream enzyme of redox signal pathway in heart and a major target of oxidative attack occurred during chronic myocardial infarction and consequent heart failure complicated by aging. Impairment and down-regulation of cardiac HCCS is closely related to myocardial infarction-caused heme defect, associated mitochondrial dysfunction and declining of cardiac resilience to development of heart failure during aging process. The disease model of chronic infarction associated heart failure will be created by the animal surgery of in vivo occlusion of mouse heart for 30-min and followed by in vivo chronic reperfusion for 4 weeks. Cardiac-specific HCCS transgenic mice (HCCS-tg) will be employed to evaluate if gain of HCCS function in the myocardium can promote myocardial adaptation to chronic ischemia and reperfusion and enhance cardiac mitochondrial function, preserve mitochondrial health, and improve healthspan via preserving heme integrity. Mitochondrial function in the mouse heart will be measured using oxygen polarography and kinetic assays of the enzymatic activities from electron transport chain. Echocardiography will be used to measure the cardiac function and determine cardiac resilience to chronic ischemia and reperfusion. The progress of this project will advance our knowledge toward understanding cardiac adaptation to pathological conditions of ischemia and reperfusion and promote cardiac resilience to chronic post-ischemic reperfusion as well as aging-induced heart failure with benefits of improving human healthspan.
William Chilian, Ph.D., FAVA, FCVS, and Patrick Kang, Ph.D.
Mitochondrial Disease-in-a-Dish
Mutations in more than 250 genes are known to cause mitochondrial disease. However, the genotype-phenotype association (connection between the mutation and the manifestation of the disease) is complicated; some genetic variants may be counteracted or be aggravated by other genes or environmental factors and result in diverse clinical progressions and outcomes. This genetic diversity complicates the employment of a single preclinical model which is incapable of representing all mitochondrial diseases. Moreover, with this genetic diversity it is likely that the treatment is not a “one size fits all” therapy. An effective treatment for one patient may not be effective in other patients—even those with similar symptoms. Often this complexity, and ineffective treatment does not slow the progression of the disease leading rapid deterioration and the inability of the physician to try another treatment.
This research project focuses on the creation and the validation of Disease-in-a-Dish model that is tailored to simulate the complexity of individual patients with mitochondrial disease. Blood samples from patients are retrieved from our collaborator, Dr. Bruce Cohen, in the Akron Children’s Hospital. After harvesting the white blood cells (with nuclei), these nucleated blood cells are reprogramed into induced Pluripotent Stem (iPS) cells for rapid proliferation. Using specific factors and conditions, the iPS cells are differentiated into Cardiomyocytes (CMs), a cell type of high energetic metabolism, which renders it ideal to study the characteristics of the mitochondrial dysfunction, e.g., excessive reactive oxygen species production, inadequate ATP production, and also devise a pharmacological and nutritional therapy to optimize mitochondrial function in each patient. A cocktail of metabolic substrates and drugs can be empirically determined to better mitochondrial function of the particular iPS-CMs. We believe this iPS cell-based platform represents a confluence of evidence-based and precision medicine and will provide in new direction in treating patients with mitochondrial diseases.
The goal is to answer the clinically relevant question: Are iPS-CMs a suitable model to study mitochondrial disease, serving a surrogate for patients with the affliction? The overreaching goal is to tailor the best cocktail for each patient.
Feng Dong, Ph.D.
Role of CXCR4 in Cardiovascular Diseases
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 is a key adaptation in the diabetic heart). Furthermore, our preliminary results also 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 and left ventricular hypertrophy. This proposal leverages novel models of loss of CXCR4 function in different cells (cardiomyocytes and endothelial cells) to investigate the role of the SDF-1: CXCR4 pathway in cardiovascular diseases and define the mechanisms of how CXCR4 knockout could affect cardiac function in animals with/without diabetes.
Jessica Ferrell, Ph.D.
HTGR5 & 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, non-alcoholic fatty liver disease (NAFLD) 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.
James Hardwick, Ph.D.
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 is 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 strategy 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.
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 FOXA3 in Alcoholic Liver Disease
Forkhead box O group A3 (FOXA3) plays an important role in liver regeneration and metabolism. So far, the role of FOXA3 in the pathogenesis of alcoholic liver disease (ALD) is unknown. In this project, we plan to use mice lacking FOXA3 and mice over-expressing FOXA3 to investigate the role of FOXA3 in ALD. The mice will be subjected to an NIAAA alcohol diet for 2 weeks. We will investigate whether FOXA3 protects against 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).
