Mechanisms of Scar-Free Healing in the Fetal Artery

描述（由申请人提供）：申请人寻求成为一个优秀的外科医生科学家。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和贝勒医学院（Baylor College of Medicine）接受了普通外科和小儿外科的培训。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手术培训，重点研究细胞粘附受体和胎儿皮肤修复。自从加入了在哈佛大学的教师，他继续高质量的基础研究，尽管有大量的临床职责。为了发展他的研究事业，并使过渡到独立，他寻求更多的时间致力于基础研究，这将是可能的这个奖项。研究环境是由白细胞生物学科在韦恩史密斯博士的指导下提供的，将提供机会学习新的和先进的研究技术，并作为一个独立的研究者成熟。该提议源于申请人的广泛目标，即理解促进胎儿动脉无瘢痕愈合的机制。在机械或化学损伤后，成人动脉愈合时伴有炎症、新生内膜增生和瘢痕，这些过程导致血管狭窄和闭塞。受伤的胎儿动脉如何愈合此前尚未描述。由于胎儿皮肤具有愈合而无瘢痕的能力，申请人假设胎儿动脉具有类似的独特修复能力，其在数量和质量上均不同于成人动脉。申请人已使用胎儿手术技术开发了胎羊颈动脉愈合的新模型。该模型的初步数据显示，胎儿动脉愈合时明显没有白细胞浸润，也没有晚期新生内膜增生和瘢痕。在本提案中，申请人计划使用该体内模型，使用电子显微镜、免疫组织化学、原位杂交、实时PCR和其他细胞和分子技术系统地表征损伤的胎羊动脉的愈合。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学和细胞差异，2）确定未损伤和损伤的胎儿和成人动脉之间细胞因子和趋化因子基因调节的差异，和3）鉴定胎儿内皮细胞的独特特征，其允许剥脱内膜的快速再内皮化而不诱导炎症和瘢痕。申请人的目标是确定胎儿动脉中促进再生并防止炎症和瘢痕的关键机制。他的长期目标是将这些知识应用于儿童和成人的临床，以限制血管炎症，新生内膜增生和瘢痕形成。

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.