Mechanisms of Scar-Free Healing in the Fetal Artery

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DESCRIPTION (provided by applicant): The applicant seeks to become a superb surgeon-scientist. After graduating from Stanford University and UCLA School of Medicine, he trained in general surgery at UCSF and pediatric surgery at Baylor College of Medicine (BCM). During training he completed a 3-year research fellowship at the Children's Hospital of Philadelphia where he was trained in fetal surgery and focused on cell adhesion receptors and fetal skin repair. Since joining the faculty at BCM he has continued quality basic research despite having substantial clinical duties. To develop his research career and to make the transition to independence, he seeks more time commitment to basic research, something that would be made possible by this award. The research environment that is provided by the Section of Leukocyte Biology at BCM under the mentorship of Dr. Wayne Smith will offer opportunities to learn new and advanced research techniques and to mature as an independent investigator. This proposal stems from the applicant's broad goal of understanding mechanisms that promote scar-free healing in fetal arteries. Following mechanical or chemical injury, adult arteries heal with inflammation, neointimal hyperplasia and scar, processes which lead to vessel narrowing and occlusion. How injured fetal arteries heal has not been previously described. Because fetal skin has the ability to heal without scar, the applicant hypothesizes that fetal arteries possess similar unique reparative capabilities that are both quantitatively and qualitatively different from those seen in adult arteries. The applicant has used fetal surgery techniques to develop a novel model of carotid artery healing in fetal lambs. Preliminary data from this model shows that fetal arteries heal with a striking absence of leukocyte infiltrate, and lack of late neointimal hyperplasia and scar. In this proposal the applicant plans to use this in vivo model to systematically characterize healing in the injured fetal sheep artery using electron microscopy, immunohistochemistry, in situ hybridization, real-time PCR and other cellular and molecular techniques. The specific aims include: 1) further defining morphologic and cellular differences between healing fetal and adult arteries, 2) determining differences in cytokine and chemokine gene regulation between uninjured and injured fetal and adult arteries, and 3) identifying the unique characteristics of fetal endothelial cells that permit rapid reendothelialization of the denuded intima without inducing inflammation and scar. The applicant's goal is to identify the critical mechanisms in the fetal artery that promote regeneration and prevent inflammation and scar. His long term objective is to apply this knowledge clinically in both children and adults to limit vascular inflammation, neointimal hyperplasia and scarring.