TRAINING IN PHARMACOLOGY, TOXICOLOGY & PHARMACEUTICAL SCIENCES 2008 ASPET SUMMER UNDERGRADUATE RESEARCH FELLOWSHIP OPPORTUNITY at the UNIVERSITY OF CINCINNATI
The Department of Pharmacology & Cell Biophysics, College of Medicine is pleased to offer this research project as part of the 2008 summer ASPET SURF Training Program offered  by the Department of Pharmacology & Cell Biophysics.  Students interested in this project are advised to contact Professor Matlib to discover more about the project, learn what your responsibilities will be during the ten-week research training program.
2008 ASPET SURF Project #:  08 - 004 Faculty Supervisor/Mentor: Mohammed A. Matlib, Ph.D. Professor Pharmacology & Cell Biophysics College of Medicine, University of Cincinnati Email:  matlibma@uc.edu
Project Title: Mitochondrial FAGEX Modulation of Lipotoxic-Diabetic                                       Cardiomyopathy
Research Program Description:  The incidence of heart failure have been increasing accompanying with alarming increases in the most (90-95%) common type 2 diabetes associated with obesity in recent years in the USA.  The intracellular lipid accumulation and associated toxicity in myocytes led to call this complication as lipotoxic cardiomyopathy.  Excess long-chain fatty acids in obesity and type 2 diabetes causes overproduction of their metabolites in cardiac myocytes.  Abnormal levels of long-chain acyl-carnitine and acyl-CoA inhibit their beta-oxidation in mitochondria, ADP/ATP transport, ion transport, and some critical membrane-bound enzyme activities.  These metabolites also induce various cell injuries.      Matlib et al. recently discovered a novel system that breaks down acyl-carnitine and acyl-CoA to free fatty acid (FA) and then export it from heart mitochondria (Gerber et al. 2006).  Activation of this FA generation and export (FAGEX) system is likely to prevent accumulation of acyl-carnitine and acyl-CoA in mitochondria and thus myocytes.      Our central hypothesis is that inactivation of FAGEX will cause, and activation of FAGEX will prevent, lipotoxic cardiomyopathy.  In testing this hypothesis, we use gene-targeted and transgenic mouse models in combination with pharmacological activation or inhibition of the FAGEX to identify the constituent and regulatory protein(s) and their role in lipotoxic cardiomyopathy.  We developed a direct assay for the measurement of rate of FAGEX in mitochondria isolated from individual mouse hearts.  We use gene-targeted mouse models for clinically relevance because obese and diabetic individuals carrying dominant negative mutation(s) in gene(s) of FAGEX constituent protein(s) would be most likely to be susceptible to lipotoxic cardiomyopathy. Our study may ultimately lead to the identification of human gene(s) responsible for lipotoxic cardiomyopathy.  Results may lead to a novel therapeutic approach for obese and type 2 diabetic patients afflicted with cardiomyopathy and heart failure.
ASPET SURF Project Description: The ASPET SURF student will be offered two projects in the Matlib laboratory. (1) Identify the protein(s) that exports free fatty acid from mitochondrial matrix.  Mitochondrial anion carriers, adenine nucleotide (ATP/ADP) transporter (ANT), dicarboxylate transporter (DCT), and uncoupling protein-2 (UCP-2) and UCP-3 are candidate proteins for the export of free fatty acid anion (FFA^-) from mitochondrial matrix.  To identify which protein is involved in FFA^- export, we will test whether or not inhibitors of these proteins inhibit export of palmitic acid from heart mitochondria isolated from normal and UCP-3 gene knockout mice and UCP-3 over-expressed mice. (2) Determine ANT, DCT, UCP-3 and UCP-2 protein level in explanted failing hearts of obese/type 2 diabetic mice.  Our hypothesis is that decreased FAGEX activity and its constituent proteins accompany increased levels of acyl-carnitine and acyl-CoA in failing hearts.  Frozen ventricular muscle obtained from heart-transplant patients will be examined by Western blot to determine whether or not ANT, DCT, UCP-2 or UCP-3 protein level is decreased in failing hearts of obese/diabetic individuals.