Selectins and Fetal wound Healing

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DESCRIPTION (provided by applicant): The overall objective of this project is to gain an in depth understanding into the role of selectins in the modulation of the inflammatory response following wounding in the adult and fetus. Fetal dermal wound healing is characterized by a scant inflammatory response and minimal fibrosis. Although fetal inflammatory cells are generally considered immature, an acute inflammatory response (with fibrosis) can be evoked at the site of fetal wounds by the application of diverse stimuli. Selectins are cell surface lectin molecules expressed on both leukocytes and endothelial cells that interact with their respective carbohydrate ligands to facilitate the early events of leukocyte recruitment, and thereby, contribute significantly to the inflammatory process. The contributions of these adhesion molecules to wound closure, repair and scar formation are poorly understood. This study is therefore proposed to evaluate the role of selectins in wound healing. The application will be centered on the hypothesis that the minimal inflammation noted in fetal dermal wounds is a consequence of alterations in expression of P- and E-selectin on fetal platelets and endothelial cells. To test this hypothesis, the relative expression of selectins on adult and fetal platelets and endothelial cells will be determined. Mice with targeted deletions of individual or combinations of selectins will be studied to determine the consequences of selectin absence on wound healing. Using the murine syngeneic fetal skin transplantation model and creating mice chimeric for selectins, the specific contributions of platelet or endothelial selectins in the inflammatory response will be elucidated. Understanding the mechanism of scarless fetal wound healing will provide alternative avenues to modulate the postnatal wound healing response. This will have implications not only in the management of complications of dermal wound healing (bum contractures, keloids, hypertrophic scars, non-healing ulcers, etc.) but also in all conditions where fibrosis is an undesired consequence, such as pulmonary fibrosis, strictures, peritoneal adhesions, hepatic fibrosis, etc. Furthermore, understanding how selectins modulate the inflammatory response in the fetus will reveal valuable information that may explain the predisposition of neonates and premature infants to infections. These may then provide opportunities to assist with the inflammatory responses in these children when they are most vulnerable.