Role of Vitamin D in Lung Development and Bronchopulmonary Dysplasia

临床问题：支气管肺发育不良（BPD），早产儿的慢性肺部疾病， 与严重的呼吸系统并发症有关，这些并发症会持续到成年。BPD源于中断 肺血管和肺泡生长。最近的研究表明维生素D在胎儿肺中起作用 在绒毛膜炎的动物模型中，本发明的化合物用于肺发育并增强肺发育。但 维生素D促进血管和肺泡生长的机制仍不清楚。 候选人：我是儿科系的助理教授，也是委员会认证的新生儿医生 在科罗拉多大学医学院。我对维生素D对肺生长和 功能是第一次证明了一个惊人的保护作用，早期维生素D治疗的动物 BPD模型，并进一步表明至少部分这些作用是通过增强或保留 肺损伤后促血管生成信号机制。我的短期目标：1）增进我的理解 以及利用小鼠遗传学研究维生素D和肺发育的机制调节; 2）开发新的 分析和解释基因组和遗传数据的技能，以确定胎儿期维生素D敏感途径 肺发育; 3）扩展我在统计学和生物信息学方面的理解和技能。我的长期 职业目标是成为一个独立的医生科学家谁将有效地翻译机械 肺血管发展的基础研究，以新的见解有关的发病机制和 BPD的潜在治疗。在这个奖项的第四年，我将提交我的第一个R 01申请。 研究：根据目前的文献和我们的初步数据，这一建议的中心假设是 在实验性BPD中，异常的维生素D信号有助于异常的血管和肺泡 生长，导致PH，并增加对围产期肺损伤不良影响的易感性 结构和维生素D在发育中的肺中的促血管生成作用是通过 增加的PPARγ和VEGF信号传导。我们提出以下具体目标：目标1：确定 胎儿维生素D缺乏是否损害内皮细胞生长、功能和血管分泌信号通路， 其导致异常的血管和气腔结构，并增加对出生后高氧的易感性; 目的#2：确定围产期维生素D信号传导是否通过保护PPARγ - 内毒素暴露后胎鼠肺中的VEGF信号传导并预防BPD和PH;目的#3：确定 是否由于EC特异性维生素D受体缺乏而导致的维生素D信号传导受损破坏了肺生长， 导致PH，并增加产前（ETX）或产后（高氧）应激对肺损伤的严重程度。 环境：我有强大的多学科指导，由既定的研究人员（大学） 科罗拉多医学院和普渡大学）。我的指导团队在基本的 血管、肺和维生素D生物学研究以及先前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.