The overall aim of this project is to improve our understanding of the role of cell adhesion receptors andextracellular matrix (ECM) proteins in cardiovascular development, maintenance, repair and pathology, usingmouse models and cell biological approaches, as well as increasing use of genome-scale approaches. Ourmain interests are in heart development, angiogenesis (both physiological and pathological) andhemostasis/thrombosis. All these involve cell adhesion events and our aim is to provide a deeperunderstanding of the molecular and cellular mechanisms involved. Such an understanding has majorimplications for therapeutic approaches, since cell adhesion proteins are accessible outside cells and excellentprecedents exist for drugs that target known adhesion receptors, especially in thrombosis, inflammation andautoimmune disease. We have had long-standing collaborations on the roles of adhesion proteins ininflammation and hemostasis/thrombosis with Dr. Wagner, who is now a member of this Program Project. Weare also collaborating with Dr. Krieger, probing the contributions of adhesion of vascular cells to the models ofcoronary heart disease that he has developed. Both of those collaborations will continue in the next grantperiod and will also incorporate collaborations on angiogenesis, a topic which has been a major component ofour own research effort during the past funding period. In the next period, our collaborations will continue, withan increased focus on connections to human disease. We have many interests in common with the Lodishlab. and are planning additional collaborations during the next funding period investigating links amongadiponectins, 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, whichinteracts with the fibronectin gene during cardiac development. Identification will be by continued SNPmapping combined with the mouse HapMap, cross-correlated with expression profiling data and tested byRNA interference.2. to analyze existing strains (plus additional ones that we are generating) that are altered in theirexpression and splicing of fibronectin. Those mice will be investigated first for defects in vasculardevelopment and angiogenesis.3. that will be complemented by in vitro analyses using FN-null endothelial cells and recombinant FNisoforms 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 particularfocus 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 invivo, ex vivo and in vitro approaches continuing our longstanding interest in this question and our recentcollaborations on this topic with Dr. Wagner.6. we have initiated and will expand a collaboration with Dr. Krieger to combine our expertise on adhesionand our mouse strains altered in many relevant adhesion receptors and ECM proteins with Dr. Krieger'sexpertise in coronary heart disease (CHD) and his mouse models of CHD.
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