Mechanisms of Scar-Free Healing in the Fetal Artery

描述(由申请人提供)：应聘者希望成为一名出色的外科医生和科学家。从斯坦福大学和加州大学洛杉矶分校医学院毕业后，他在加州大学旧金山分校接受普通外科培训，并在贝勒医学院(BCM)接受儿科外科培训。在培训期间，他在费城儿童医院完成了为期3年的研究奖学金，在那里他接受了胎儿外科培训，专注于细胞黏附受体和胎儿皮肤修复。自从加入BCM的教职以来，他继续进行高质量的基础研究，尽管他有大量的临床职责。为了发展他的研究事业，并向独立过渡，他寻求更多的时间致力于基础研究，这将使这个奖项成为可能。BCM的白细胞生物学部门在韦恩·史密斯博士的指导下提供的研究环境将提供学习新的和先进的研究技术并作为一名独立研究人员成熟的机会。这一建议源于申请者的广泛目标，即了解促进胎儿动脉无疤痕愈合的机制。机械或化学损伤后，成人动脉愈合时会出现炎症、新生内膜增生和瘢痕，这些过程会导致血管狭窄和闭塞。受伤的胎儿动脉是如何愈合的，此前还没有描述。由于胎儿皮肤具有无疤痕愈合的能力，申请者假设胎儿动脉具有类似的独特修复能力，无论是在数量上还是在质量上都与成人动脉不同。申请者使用胎儿外科技术开发了一种新的胎羊颈动脉愈合模型。该模型的初步数据显示，胎儿动脉愈合时，白细胞明显减少，晚期新生的内膜增生和瘢痕明显减少。在这项提案中，申请人计划使用这一活体模型，通过电子显微镜、免疫组织化学、原位杂交、实时聚合酶链式反应和其他细胞和分子技术，系统地表征受损胎儿绵羊动脉的愈合情况。具体目标包括：1)进一步确定愈合的胎儿和成人动脉之间的形态和细胞差异；2)确定未损伤和受损的胎儿和成人动脉在细胞因子和趋化因子基因调控方面的差异；3)鉴定胎儿内皮细胞的独特特性，使剥脱的内膜快速内皮化，而不会引起炎症和疤痕。申请者的目标是确定胎儿动脉中促进再生和防止炎症和疤痕的关键机制。他的长期目标是将这一知识应用于儿童和成人的临床，以限制血管炎症、新生内膜增生和疤痕形成。

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.