Since graduating from medical school, my goal has been to become an academic surgeon with great emphasis on a career exploring basic science issues related to clinical problems. In vascular surgery, the need for improved small diameter vascular grafts has been recognized. Through the excellent research training I've received, I have developed an interest in the heterotypic endothelial (EC) and smooth muscle cell (SMC) interactions occurring within the vascular wall. I have used a SMC-EC co-culture system to model these interactions, and have developed a novel flow device to study the effect of flow on SMC-EC interactions. My objective is to further characterize the biologic mechanisms involved in this model, but I have found I lack the specific expertise in molecular biology to proceed. At Robert Wood Johnson Medical School, I have a unique opportunity to purse my career development by working with outstanding scientists in fields that will enhance my abilities and intellect. I plan to achieve my objective through course work at Rutgers University, attendance of basic science conferences, and regular meetings with my mentor and advisors designed to monitor and enhance my progress. This program will improve my fundamental knowledge base in basic science (molecular biology, biochemistry, and biomedical engineering), and allow me to expand the breadth of techniques used in my laboratory. This will allow me to continue to define the biologic mechanisms responsible for the complex cellular and cell-material interactions. Using this co-culture flow model to study heterotypic cellular and cell-matrix/biomaterial interactions in the presence of shear stress, we have observed that SMCs promote EC adhesion and adaptation to flow. We hypothesize the failure of biomaterials to support the essential processes of FC adhesion and migration is due to a lack of key matrix components, and the development of a matrix optimal for EC attachment and migration is dependent on SMC-EC communication. I now propose to study the mechanisms by which SMCs enhance EC adaptation to flow. Using BC detachment rates and migration in the co-culture flow model as bioassays, we will evaluate if SMCs enhance BC adhesion and migration by altering cell-matrix and cell-cell interactions. We will also determine if BC apoptosis is in involved in the detachment process, and whether BC apoptosis is modified by SMCs. We will partially characterize the factor(s) present in SMC conditioned media and determine by bioassays and immunodepletion if it is likely to correspond to a previously identified compound. If the factor(s) is not identified in this manner, we will continue the purification process to isolate the factor(s) and determine its identity. Conceivably, the responsible mediator(s) could be used as an adjunct in the development of new prosthetic or tissue- engineered biosynthetic grafts.
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