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TRAINING IN PHARMACOLOGY,
TOXICOLOGY & PHARMACEUTICAL SCIENCES 2009 ASPET SUMMER UNDERGRADUATE
RESEARCH FELLOWSHIP |
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The Department of Pharmacology & Cell
Biophysics, College of Medicine is pleased to offer this research project as
part of the 2009 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. |
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2009
ASPET SURF Project #: 09 - 06 Faculty
Supervisor/Mentor: Mohammed
A. Matlib, Ph.D. Professor Pharmacology
& Cell Biophysics Email: matlibma@uc.edu |
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Mitochondrial FAGEX Modulation of Lipotoxic-Diabetic
Cardiomyopathy |
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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. |
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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. |
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