Mechanisms of Scar-Free Healing in the Fetal Artery

胎儿动脉无疤痕愈合机制

• 批准号: 7082330
• 负责人: Darrell Lorne Cass
• 金额: $ 12.44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082330
• 关键词: age difference; cardiovascular injury; cell morphology; cytokine; electron microscopy; embryo /fetus; embryo /fetus surgery; immunocytochemistry; immunogenetics; in situ hybridization; inflammation; polymerase chain reaction; pregnancy circulation; scars; sheep; wound healing

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.

描述（由申请人提供）：申请人寻求成为一名优秀的外科科学家。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手术的培训，专注于细胞粘附受体和胎儿皮肤修复。自加入BCM教职员工以来，尽管有大量的临床职责，他仍继续进行高质量的基础研究。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，这将通过该奖项成为可能。在Wayne Smith博士的指导下，BCM白细胞生物学部门提供的研究环境将为学习新的和先进的研究技术提供机会，并使其成为一名成熟的独立研究者。该建议源于申请人了解促进胎儿动脉无疤痕愈合机制的广泛目标。在机械或化学损伤后，成人动脉会随着炎症、内膜增生和疤痕愈合，这些过程会导致血管狭窄和闭塞。受伤的胎儿动脉如何愈合以前没有描述过。由于胎儿皮肤具有无疤痕愈合的能力，申请人假设胎儿动脉具有与成人动脉在数量和质量上不同的类似独特的修复能力。申请人使用胎儿手术技术开发了一种胎羊羔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，也没有晚期内膜增生和瘢痕。在本提案中，申请人计划使用该体内模型，通过电子显微镜、免疫组织化学、原位杂交、实时PCR等细胞和分子技术，系统地表征受伤胎羊动脉的愈合。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和细胞差异；2)确定未受伤和受伤的胎儿和成人动脉之间细胞因子和趋化因子基因调控的差异；3)确定胎儿内皮细胞的独特特征，使脱落的内膜能够快速再内皮化，而不会引起炎症和疤痕。申请人的目标是确定胎儿动脉中促进再生和预防炎症和疤痕的关键机制。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。