Selectins and Fetal wound Healing

描述(由申请人提供)： 这个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。胎儿真皮伤口愈合的特点是炎症反应较少，纤维化程度较低。虽然胎儿炎症细胞通常被认为是不成熟的，但通过应用不同的刺激，可以在胎儿伤口处诱发急性炎症反应(伴有纤维化)。选择素是表达在白细胞和内皮细胞上的细胞表面凝集素分子，它们与各自的碳水化合物配体相互作用，促进白细胞募集的早期事件，从而在炎症过程中发挥重要作用。这些黏附分子对伤口闭合、修复和疤痕形成的作用还知之甚少。因此，本研究旨在评估选择素在伤口愈合中的作用。这项应用将集中在这样一个假设上，即胎儿皮肤伤口中注意到的轻微炎症是胎儿血小板和内皮细胞上P-和E-选择素表达变化的结果。为了验证这一假设，我们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。有针对性地删除单个或组合选择素的小鼠将被研究，以确定选择素缺失对伤口愈合的影响。利用小鼠同基因胎儿皮肤移植模型，建立小鼠选择素嵌合体，阐明血小板或内皮选择素在炎症反应中的特异性作用。了解无疤痕胎儿伤口愈合的机制将为调节出生后伤口愈合反应提供替代途径。这不仅对真皮伤口愈合的并发症(烧伤痉挛、瘢痕疙瘩、增生性疤痕、无法愈合的溃疡等)的处理有影响。而且在纤维化是不良后果的所有情况下也是如此，例如肺纤维化、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可能解释新生儿和早产儿感染易感性的有价值的信息。然后，在这些儿童最脆弱的时候，这些可能会提供机会来帮助他们做出炎症反应。

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.