Selectins and Fetal wound Healing

描述（由申请人提供）： 本项目的总体目标是深入了解选择素在成人和胎儿创伤后炎症反应调节中的作用。胎儿皮肤伤口愈合的特点是炎症反应少，纤维化程度低。虽然胎儿炎症细胞通常被认为是不成熟的，但通过施加不同的刺激，可以在胎儿伤口部位诱发急性炎症反应（伴纤维化）。选择素是在白细胞和内皮细胞上表达的细胞表面凝集素分子，其与各自的碳水化合物配体相互作用以促进白细胞募集的早期事件，从而显著促进炎症过程。这些粘附分子对伤口闭合、修复和瘢痕形成的贡献知之甚少。因此，本研究拟评估选择素在伤口愈合中的作用。该应用将集中在胎儿皮肤伤口中观察到的最小炎症是胎儿血小板和内皮细胞上P-和E-选择素表达改变的结果的假设上。为了检验这一假设，将测定成人和胎儿血小板和内皮细胞上选择素的相对表达。将研究具有选择素的单独或组合的靶向缺失的小鼠以确定选择素缺失对伤口愈合的后果。使用小鼠同基因胎儿皮肤移植模型和创建选择素嵌合小鼠，血小板或内皮选择素在炎症反应中的具体贡献将被阐明。了解无瘢痕胎儿伤口愈合的机制将提供替代途径来调节产后伤口愈合反应。这不仅在皮肤伤口愈合并发症（烧伤挛缩、瘢痕疙瘩、增生性瘢痕、不愈合溃疡等）的管理方面具有意义，而且在纤维化是不希望的结果的所有情况下，如肺纤维化、狭窄、腹膜粘连、肝纤维化等。此外，了解选择素如何调节胎儿的炎症反应将揭示有价值的信息，可以解释新生儿和早产儿感染的易感性。然后，这些可能提供机会，以帮助这些儿童在他们最脆弱的时候炎症反应。

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.