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

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于培养独立的医生-科学家。申请人是儿科的初级教师，她的导师是约书亚黑尔博士，医学教授，迈阿密大学米勒医学院跨学科干细胞研究所所长。心血管疾病干细胞再生疗法领域的领导者。Hare博士培养了许多初级科学家，博士后研究员和研究生。本提案中描述的课程将为申请人提供获得干细胞生物学和新生儿心肺生理学更强科学背景的机会。申请人的研究将侧重于了解c-kit在新生儿缺氧诱导的肺动脉高压（PH）发展中的作用。PH每年影响约1/1000的新生儿，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，主要作为干细胞标志物进行研究;然而，其在PH中的作用尚不清楚。我们的初步数据表明，增加c-kit细胞在肺动脉和右心室（RV）的新生小鼠与PH。我们假设，c-kit细胞参与缺氧诱导的肺血管重构a）分化成肌成纤维细胞或B）指导血管生成，促有丝分裂和生存因子的分泌，加剧肺血管重构。具体目标是：1）观察慢性缺氧性肺动脉高压新生小鼠肺血管中天然和骨髓源性c-kit细胞的表型和时空分布; 2）阐明慢性缺氧性肺动脉高压新生小鼠肺血管中c-kit细胞归巢和活化的调控机制; 3）探讨c-kit细胞是否参与慢性缺氧性肺动脉高压的形成。kit祖细胞通过分化成成熟的肺血管细胞或通过分泌促有丝分裂因子、促血管生成因子和存活因子参与PH。迈阿密大学医学院是这个培训项目的理想环境，因为它拥有最先进的资源和不同背景的领先科学家的独特组合。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。预计该奖项将使候选人成为具有心肺和干细胞生物学专业知识的独立调查员。相关性（参见说明）：最近，已经出现了一系列新的治疗方式，血管扩张的肺血管，但很少有显着降低血管重塑，这是明显的PH。这些研究将扩大我们的基本知识的干细胞在新生儿肺血管重塑的作用，并提供了一个坚实的基础，为发展新的治疗策略。 (End摘要）

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)