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怀孕期间维生素D缺乏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之一，在时空上调节围产期肺成熟。然而，怀孕期间维生素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增强了围产期肺成熟，因此维生素D的缺乏会扰乱正常的肺结构和功能发育，这与后代的哮喘表型一致，提供了维生素D缺乏与儿童哮喘之间令人信服的机制联系。我们假设妊娠期和围产期维生素D缺乏会特异性地改变体内平衡的甲状旁腺激素相关蛋白/过氧化物酶体增殖物激活受体？（PTHrP/PPAR?）信号在发育中的肺中，导致近端和远端气道的肌源性表型增强，并且在怀孕期间补充足够的维生素D可阻止后代哮喘的发展。利用维生素D缺乏症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PTHrP/PPAR介导的肺泡上皮-间质相互作用中的作用。导致表面活性剂合成增加和肺泡分隔的信号；2)近端气道平滑肌分化；3)孕期和哺乳期补充维生素D是否能预防与维生素D缺乏相关的肺部形态、结构和功能变化，从而防止后代患哮喘的易感性。本研究首次批判性地评价了维生素D在围产期肺成熟中的生理作用，并为补充维生素D预防儿童哮喘的生物学原理和机制基础提供了新的认识，儿童哮喘是儿童发病率和死亡率的主要原因。这些研究对于确定维生素D的最佳剂量至关重要，甚至更好的是，找到维生素D类似物或代谢物，具有最佳的呼吸作用，没有任何明显的副作用。此外，由于哮喘的起源是遗传和环境的，这些研究可以为发现PTHrP/PPAR的遗传变异提供基础。以及决定维生素D对儿童哮喘影响的Wnt信号通路。

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.