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COCVD INVESTIGATORS
PILOT PROJECT
Role of bioactive lipids in the protective pathways of obesity in ischemic
cardiomyopathy
 Ahmed
Abdel-Latif. M.D.
Assistant Professor
Division of Cardiology
Department of Internal Medicine
Obesity is approaching epidemic state in the western world and is a known risk
factor for acute myocardial infarction (AMI). AMI and the subsequent ischemic
heart disease (IHD) are often complicated with high mortality and poor overall
prognosis despite significant advances in medical therapy and revascularization
strategies. Currently, short of heart transplantation with all of its inherit
limitations, there are no available treatment strategies that replace the
infracted myocardium and therapies are largely palliative. Paradoxically,
obesity may also confer a protective effect against AMI-associated remodeling
which leads to IHD. The molecular basis for this protection is poorly
understood. AMI initiates poorly understood innate reparatory mechanisms through
which BMSPCs are mobilized and home towards the ischemic myocardium contributing
to myocardial regeneration and correlating with cardiac recovery. Our
preliminary data indicates that bioactive lipids such as sphingosine-1 phosphate
(S1P), but not traditional chemokines, play a quintessential role in this
mobilization and homing. Interestingly, obesity and the associated metabolic
syndrome are associated with alterations in bioactive lipids’ metabolism. Our
objective in this application, therefore, is to develop better understanding of
the obesity-associated alterations in AMI-induced stem cell mobilization
pathways, specially those involving bioactive lipids, and devise therapies that
harness this process for therapeutic myocardial regeneration strategies. Our
central hypothesis has been formulated based upon the existing literature and
our strong preliminary data demonstrating that BMSPCs express S1P receptors and
will migrate towards plasma from AMI patients in an S1P dependent fashion. Our
rationale for these studies is that understanding the protective role of
bioactive lipids and stem cell mobilization during AMI in obesity would help
establish a strong scientific framework for eventual generalizable human
myocardial regenerative clinical trials utilizing the available and new
pharmacological modulators of bioactive lipids and their receptors. In addition
to clinical studies, our approach will exploit small molecule-strategies in
mouse models through examining the obesity associated molecular and cellular
pathways, specially those involving bioactive lipids, that are activated by
myocardial infarction (Aim 1); and examine the modulation of bioactive lipids’
metabolism and receptor expression to enhance cardiac recovery following AMI
(Aim 2).
PROJECT MENTORS
 Susan
Smyth, M.D., Ph.D.
Professor and Chief of Cardiovascular Medicine
Department of Internal Medicine
 Andrew
Morris, Ph.D.
Professor
Division of Cardiology
Molecular and Cellular Biochemistry
Department of Internal Medicine
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