DHSA Pilot Projects:
Project Title: "JAM-A - A Potential Risk Factor for Dilated Cardiomyopathy"
Co-Investigators: Ulhas P. Naik, UD, Takeshi Tsuda, Nemours, Walter Koch, TJU, and William Weintraub, Christiana Care
Background and Significance:
In patients with age related dilated cardiomyopathy (DCM) the LV chambers are dilated, the walls are thin and the heart has an overall poor contractility. The genetic determinants that may be responsible for DCM are not known. There are no good animal models to study the disease. Junctional Adhesion Molecule-A (JAM-A), a member of the Ig family of molecules is localized at tight junctions of endothelial and epithelial cells and on the surface of neutrophils, monocytes, lymphocytes and platelets. JAM-A has been shown to play a role in leukocyte transmigration, mononuclear cell recruitment to inflamed atherosclerotic endothelium, platelet aggregation, and FGF-2 induced cell migration and angiogenesis. In mouse models of inflammatory peritonitis, cardiac and hepatic ischemia-reperfusion injury, the degree of injury to the heart or liver respectively is increased in JAM-A knock out (K/O) mice compared to the Wild Type (WT) mice. After myocardial infarction (MI), survival of JAM-A null mice is significantly reduced compared to WT mice. We also find that JAM-A null mice show age related dilated cardiomyopathy. The plasma levels of VEGF in these mice are elevated age dependently. Thus JAM-A null mice could be an excellent model for studying both dilated cardiomyopathy and myocardial infarction survival.
The goals of this proposal are:
- To understand the molecular mechanism of dilated cardiomyopathy and survivalafter MI. JAM-A null mice were generated in Dr. Naik’s laboratory and Dr. Fomin will be overseeing these studies. In collaboration with Dr. Tsuda and Dr. Gao MI survival studies were performed. Dr Wally Koch's lab and the Center for Translational Medicine have world-class expertise in cardiac physiology, biochemistry, morphology, etc. They can interrogate anything from a single cell to an entire heart using an array of state-of-the-art technology that is not available anywhere in the U.S. They also have the ability to isolate single myocytes for electrophysiology, can holter monitor and exercise mice, have confocal imaging for immunohistochemistry, and a gene therapy core in order to alter JAM-A levels in order to attempt to reverse the phenotype.
- To screen patients whose plasma levels of VEGF are elevated for SNPs or mutations in JAM-A gene and make a correlation for JAM-A mutation/expression to risk of developing dilated cardiomayopathy and/or poor survival after MI. For this, human tissue samples will be obtained through the collaboration with Dr. Koch, TJU. TJU has nearly 1400 specimens from patients enrolled in STICH. They also have a large collection of DNA from normal volunteers without CV disease, patients with idiopathic dilated caridomyopathy, and patients with ischemic heart disease in which, we will look for polymorphisms in the JAM-A gene. Clinical outcomes studies will be performed by Dr. Weintraub at Christiana Cardiovascular Outcomes Research Center.
Specific Aims:
The goal of this proposal is to build up translational research program studying biological significance of JAM-A and its relationship to post-MI complications. The proposal includes three goals.
- Aim 1: Basic research using animal models.
- Aim 2: JAM-A and its related gene expression in the human myocardial samples.
- Aim 3: Clinical outcome study with patients with acute MI admitted to CICU.