The Role of c-kit in the Pathogenesis of Neonatal Pulmonary Hypertension

描述(由申请人提供)：本建议书描述了一项为期5年的培养独立内科医生-科学家的培训计划。申请者是儿科学的初级教员，她的导师是迈阿密大学米勒医学院跨学科干细胞研究所主任、医学教授约书亚·黑尔博士。心血管疾病干细胞再生疗法领域的领先者。黑尔博士培养了许多初级教职科学家、博士后研究员和研究生。这项建议中描述的课程将为申请者提供在干细胞生物学和新生儿心肺生理学方面获得更强的科学背景的机会。申请人的研究将集中在了解c-kit在新生儿缺氧性肺动脉高压(PH)发展中的作用。每年每1000名新生儿中就有1人受到影响，并且仍然是该人群死亡的主要原因之一，c-kit是一种酪氨酸激酶受体，主要作为干细胞标记物进行研究；然而，它在PH中的作用尚不清楚。我们的初步数据显示，肺动脉高压新生小鼠的肺动脉和右心室(RV)中c-kit细胞增加。我们推测c-kit细胞通过a)分化为肌成纤维细胞或b)分泌血管生成因子、有丝分裂生成因子和生存因子而参与低氧诱导的肺血管重构，从而加剧肺血管重构。具体目的是：1)研究慢性缺氧性肺高压新生小鼠肺血管中天然和骨髓来源c-kit细胞的表型和时空分布。2)探讨新生儿慢性低氧性肺高压时c-kit细胞归巢和活化的调控机制。3)探讨c-kit前体细胞是否通过分化为成熟的肺血管细胞或分泌促有丝分裂因子、血管生成因子和存活因子参与肺高压。迈阿密大学医学院是这一培训计划的理想环境，因为它拥有最先进的资源和不同背景的顶尖科学家的独特组合。拟议的研究培训计划将包括参加教学课程，以及由专家咨询委员会定期审查候选人的进展情况。预计这一奖项将使候选人成为一名拥有心肺和干细胞生物学专业知识的独立研究员。相关性(见说明)：最近，已经有一系列新的治疗方法扩张了肺血管，但很少有明显减少在PH期间明显的血管重塑。这些研究将扩大我们对干细胞在新生儿肺血管重塑中作用的基础知识，并为开发新的治疗策略提供坚实的基础。(摘要结束)

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an independent physician- scientist. The applicant is a junior faculty in Pediatrics and her mentor is Dr. Joshua Hare, Professor of Medicine, and Director of the Interdisciplinary Stem Cell Institute at the University Of Miami Miller School Of Medicine. A leader in the field of stem cell regenerative therapies for cardiovascular disease. Dr. Hare has trained many junior faculty scientists, postdoctoral fellows and graduate students. The curriculum described in this proposal will provide the applicant with the opportunity to acquire a stronger scientific background in stem cell biology as well as neonatal cardiopulmonary physiology. The applicant's research will focus on understanding the role of c-kit in the development of neonatal hypoxia-induced pulmonary hypertension (PH). PH affects approximately 1 in 1000 neonates per year and remains one of the leading causes of mortality in this population, c-kit is a tyrosine kinase receptor which is mainly studied as a stem cell marker; however its role in PH is unknown. Our preliminary data have demonstrated increased c-kit cells in the pulmonary arteries and right ventricles (RV) of neonatal mice with PH. We hypothesize that c-kit cells participate in hypoxia-induced pulmonary vascular remodeling by a) differentiating into myofibroblasts or b) directing the secretion of angiogenic, mitogenic and survival factors which exacerbate pulmonary vascular remodeling. The specific aims are: 1) To characterize the phenotype and temporal-spatial distribution of native and BM-derived c-kit cells in the pulmonary vasculature of neonatal mice with chronic hypoxia- induced PH. 2) To elucidate the mechanisms which regulate the homing and activation of c-kit cells during neonatal chronic hypoxia-induced PH. 3) To determine whether c-kit progenitor cells participate in PH by differentiating into mature pulmonary vascular cells or by secreting mitogenic, angiogenic and survival factors. The University Of Miami School Of Medicine is the ideal environment for this training program as it has the unique combination of state of the art resources and leading scientists of diverse backgrounds. The proposed research training plan will include participation in didactic courses, as well as regular reviewing of the candidate's progress by an expert advisory committee. It is expected that this award will allow the candidate to become an independent investigator with expertise in cardiopulmonary and stem cell biology. RELEVANCE (See instructions): Recently, there has been a flurry of new therapeutic modalities which have vasodilated the pulmonary vasculature, but few have significantly decreased the vascular remodeling that is evident during PH. These studies will expand our fundamental knowledge of the role of stem cells in neonatal pulmonary vascular remodeling and provide a solid foundation for the development of novel therapeutic strategies. (End of Abstract)