Cell Adhesion in Cardiovascular Biology and Pathology

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The overall aim of this project is to improve our understanding of the role of cell adhesion receptors and extracellular matrix (ECM) proteins in cardiovascular development, maintenance, repair and pathology, using mouse models and cell biological approaches, as well as increasing use of genome-scale approaches. Our main interests are in heart development, angiogenesis (both physiological and pathological) and hemostasis/thrombosis. All these involve cell adhesion events and our aim is to provide a deeper understanding of the molecular and cellular mechanisms involved. Such an understanding has major implications for therapeutic approaches, since cell adhesion proteins are accessible outside cells and excellent precedents exist for drugs that target known adhesion receptors, especially in thrombosis, inflammation and autoimmune disease. We have had long-standing collaborations on the roles of adhesion proteins in inflammation and hemostasis/thrombosis with Dr. Wagner, who is now a member of this Program Project. We are also collaborating with Dr. Krieger, probing the contributions of adhesion of vascular cells to the models of coronary heart disease that he has developed. Both of those collaborations will continue in the next grant period and will also incorporate collaborations on angiogenesis, a topic which has been a major component of our own research effort during the past funding period. In the next period, our collaborations will continue, with an increased focus on connections to human disease. We have many interests in common with the Lodish lab. and are planning additional collaborations during the next funding period investigating links among adiponectins, fibronectins and integrins. Our main aims will be as follows:- 1. to identify a modifier gene(s) (QTL) that we have mapped to a 5Mbp region on chromosome 4, which interacts with the fibronectin gene during cardiac development. Identification will be by continued SNP mapping combined with the mouse HapMap, cross-correlated with expression profiling data and tested by RNA interference. 2. to analyze existing strains (plus additional ones that we are generating) that are altered in their expression and splicing of fibronectin. Those mice will be investigated first for defects in vascular development and angiogenesis. 3. that will be complemented by in vitro analyses using FN-null endothelial cells and recombinant FN isoforms to test at the cell biological level their effects on the cells. 4. we will continue to investigate in depth the roles of various integrins in angiogenesis, with particular focus on integrins that act as FN receptors in the vasculature. 5. we will investigate contributions of FN and its splice isoforms to hemostasis and thrombosis using in vivo, ex vivo and in vitro approaches continuing our longstanding interest in this question and our recent collaborations on this topic with Dr. Wagner. 6. we have initiated and will expand a collaboration with Dr. Krieger to combine our expertise on adhesion and our mouse strains altered in many relevant adhesion receptors and ECM proteins with Dr. Krieger's expertise in coronary heart disease (CHD) and his mouse models of CHD.