Molecular Basis of Childhood Asthma Following Perinatal Vitamin D Deficiency

描述（由申请人提供）：有强有力的流行病学数据表明妊娠期维生素D缺乏症与儿童哮喘之间存在联系。此外，有强有力的实验动物数据表明，维生素D是局部肺泡旁分泌因子，时空调节围产期肺成熟。然而，妊娠期维生素D缺乏与儿童哮喘之间的机制联系尚不清楚。我们的初步数据表明，维生素D增强围产期肺成熟，使其缺乏会扰乱正常的肺结构和功能发育的方式是一致的，在后代的哮喘表型，维生素D缺乏症和儿童哮喘之间提供了一个令人信服的机制联系。我们假设，维生素D缺乏在怀孕期间和围产期特别改变稳态甲状旁腺激素相关蛋白/过氧化物酶体激活受体？（PTHrP/PPAR？）在发育中的肺中的信号传导，导致近端和远端气道中增强的肌原性表型，并且在怀孕期间补充足够的维生素D阻止后代哮喘的发展。使用维生素D缺乏的大鼠模型和最先进的分子工具，我们将确定维生素D在促进1）由PTHrP/PPAR介导的肺泡上皮-间质相互作用中的作用？2）近端气道平滑肌分化;以及检查3）妊娠和哺乳期补充维生素D是否会预防与维生素D缺乏相关的形态、结构和功能性肺变化，从而预防后代发生哮喘的易感性。拟议的研究，第一次，批判性地评估维生素D在围产期肺成熟的生理作用，并可能提供新的理解的生物学原理和机制的基础上补充维生素D，以预防儿童哮喘，一个主要的贡献者儿童发病率和死亡率。这些研究对于确定维生素D的最佳剂量至关重要，甚至更好地找到具有最佳呼吸作用而没有任何显著副作用的维生素D类似物或代谢物。此外，由于哮喘是遗传和环境的起源，这些研究可以提供基础，以寻找遗传变异的PTHrP/PPAR？和Wnt信号通路决定维生素D对儿童哮喘的影响。 公共卫生相关性：有强有力的流行病学数据表明，妊娠期维生素D缺乏症与儿童哮喘之间存在联系。然而，这种关联的潜在机制尚不清楚。拟议的研究首次严格评估了维生素D在肺成熟中的作用，并可能为补充维生素D预防儿童哮喘提供生物学原理和机制基础，这是儿童发病率和死亡率的主要因素。

DESCRIPTION (provided by applicant): There are strong epidemiologic data suggesting a link between vitamin D deficiency during pregnancy and childhood asthma. Furthermore, there are strong experimental animal data showing that vitamin D is one of the local alveolar paracrine factors that spatiotemporally modulates perinatal pulmonary maturation. However, the mechanistic link between vitamin D deficiency during pregnancy and childhood asthma is not known. Our preliminary data show that vitamin D augments perinatal lung maturation such that its deficiency would perturb normal lung structural and functional development in a way that is consistent with the asthma phenotype in the offspring, providing a compelling mechanistic link between vitamin D deficiency and childhood asthma. We hypothesize that vitamin D deficiency during pregnancy and perinatal periods specifically alters homeostatic Parathyroid Hormone-related Protein/Peroxisome Proliferator-Activated Receptor ? (PTHrP/PPAR?) signaling in the developing lung, resulting in an enhanced myogenic phenotype in both proximal and distal airways, and supplementing with sufficient vitamin D during pregnancy blocks the development of asthma in offspring. Using a rat model of vitamin D deficiency and state-of-the-art molecular tools, we will determine the role of vitamin D in promoting 1) alveolar epithelial-mesenchymal interactions mediated by PTHrP/PPAR? signaling that lead to increased surfactant synthesis and alveolar septation; 2) proximal airway smooth muscle differentiation; and examine 3) if vitamin D supplementation during pregnancy and lactation will prevent morphological, structural, and functional pulmonary changes associated with vitamin D deficiency, and hence the consequent predisposition to asthma in offspring. The proposed studies, for the first time, critically evaluate the physiologic role of vitamin D in perinatal pulmonary maturation and could provide novel understanding for the biologic rationale and mechanistic basis for vitamin D supplementation to prevent childhood asthma, a major contributor to childhood morbidity and mortality. These studies are essential to determine the optimal dose of vitamin D, or even better, to find vitamin D analogs or metabolites with optimal respiratory effects without any significant side effects. Furthermore, since asthma is both genetic and environmental in origin, these studies can provide the basis to find genetic variants in PTHrP/PPAR? and Wnt signaling pathways that determine vitamin D's effect on childhood asthma. PUBLIC HEALTH RELEVANCE: There are strong epidemiologic data suggesting a link between vitamin D deficiency during pregnancy and childhood asthma. However, the underlying mechanism for this association is not known. The proposed studies for the first time critically evaluate the role of vitamin D in lung maturation and are likely to provide a biologic rationale and mechanistic basis for vitamin D supplementation to prevent childhood asthma, a major contributor to childhood morbidity and mortality.