Role of Vitamin D in Lung Development and Bronchopulmonary Dysplasia

临床问题：支气管肺发育不良(BPD)，早产儿慢性肺部疾病 与持续到成年期的严重呼吸道并发症有关。BPD是一次中断的结果 在肺血管和肺泡的生长中。最近的研究表明维生素D在胎儿肺中起作用 绒毛膜羊膜炎动物模型的发育和增强肺发育。然而， 维生素D促进血管和肺泡生长的机制尚不清楚。 应聘者：我是小儿科的助理教授，也是注册的新生儿专家 在科罗拉多大学医学院。维生素D对小鼠肺生长和肺功能影响的研究 功能是第一个显示出早期维生素D治疗对动物有显著保护作用的人 BPD的模型，并进一步表明，这些影响中至少有一部分是通过增强或保留来调节的 肺损伤后促血管生成的信号机制。我的短期目标：1)增进我的理解 并利用小鼠遗传学研究维生素D与肺发育的调节机制；2)开发新的 分析和解释基因组和遗传数据以确定胎儿期间维生素D敏感途径的技能 肺发育；3)扩大我在统计学和生物信息学方面的理解和技能。我的长期生活 职业目标是成为一名独立的内科科学家，有效地翻译机械学 肺血管发育的基础研究对发病机制和发病机制的新认识 BPD的潜在治疗。在今年获奖期的第四年，我将提交我的第一份R01申请。 研究：根据目前的文献和我们的初步数据，这一提议的中心假设是 实验性BPD中维生素D信号的异常参与了血管和肺泡的异常 生长，引起PH，增加对围产期损伤对肺的不利影响的易感性 结构以及维生素D在发育中的肺中的促血管生成作用是通过 PPARγ和血管内皮细胞生长因子信号增强。我们提出以下具体目标：目标1：确定 胎儿维生素D缺乏是否会损害内皮细胞的生长、功能和血管分泌信号通路 导致血管和腔隙结构异常，增加出生后高氧的易感性； 目的#2：确定围产期维生素D信号是否通过保留PPARγ来改善肺结构。 内毒素暴露后胎鼠肺内血管内皮生长因子信号转导及预防BPD和PH；目的#3：确定 EC特异性维生素D受体缺乏导致的维生素D信号受损是否会扰乱肺生长， 引起肺高压，增加产前(ETX)或产后(高氧)应激所致肺损伤的严重程度。 环境：我有强大的多学科指导，由成熟的研究人员(大学 科罗拉多医学院和普渡大学)。我的指导团队在基础方面有丰富的经验 从事血管、肺和维生素D生物学研究，并有成功指导的良好记录。

The Clinical Problem: Bronchopulmonary dysplasia (BPD), the chronic lung disease of preterm infants is associated with significant respiratory complications that continue into adulthood. BPD results from a disruption in pulmonary vascular and alveolar growth. Recent studies suggest vitamin D plays a role in fetal lung development and enhances lung development in an animal model of chorioamnionitis. However, the mechanisms through which vitamin D enhances vascular and alveolar growth remain unknown. The Candidate: I am an Assistant Professor in the Department of Pediatrics, and board certified Neonatologist at the University Colorado School of Medicine. My studies on the effects of vitamin D on lung growth and function were the first to demonstrate a striking protective effect of early vitamin D treatment in an animal model of BPD, and further show that at least part of these effects are mediated through enhanced or preserved pro-angiogenic signaling mechanisms after lung injury. My short-term goals: 1) advance my understanding and use of mouse genetics to study mechanistic regulation of vitamin D and lung development; 2) develop new skills to analyze and interpret genomic and genetic data to determine vitamin D-sensitive pathways during fetal lung development; 3) expand my understanding and skills in statistics and bioinformatics. My long-term career goal is to become an independent physician scientist who will effectively translate mechanistic basic studies in pulmonary vascular development into new insights regarding the pathogenesis and potential treatment of BPD. During the fourth year of this award period, I will submit my first R01 application. The Research: Based on current literature and our preliminary data, the central hypothesis to this proposal is that abnormal vitamin D signaling in experimental BPD contributes to abnormal vascular and alveolar growth, causes PH, and increases susceptibility to the adverse effects of perinatal injury on lung structure and that the pro-angiogenic effects of vitamin D in the developing lung are mediated through increased PPARγ and VEGF signaling. We propose the following specific aims: Aim #1: To determine whether fetal vitamin D deficiency impairs endothelial cell growth, function, and angiocrine signaling pathways, which causes abnormal vascular and airspace structure, and increases susceptibility to postnatal hyperoxia; Aim #2: To determine whether perinatal vitamin D signaling enhances lung structure by preserving PPARγ – VEGF signaling in the fetal rat lung after endotoxin exposure and prevents BPD and PH; Aim #3: To determine whether impaired vitamin D signaling due to EC-specific vitamin D receptor deficiency disrupts lung growth, causes PH and increases the severity of lung injury to antenatal (ETX) or postnatal (hyperoxia) stress. The Environment: I have strong multidisciplinary mentorship by established investigators (University of Colorado School of Medicine and Purdue University). My mentoring team has extensive experience in basic vascular pulmonary and vitamin D biology research and a strong track record of prior successful mentorship.