Molecular Basis of Childhood Asthma Following Perinatal Vitamin D Deficiency

围产期维生素 D 缺乏后儿童哮喘的分子基础

• 批准号: 8176951
• 负责人: VIRENDER K REHAN
• 金额: $ 20.94万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8176951
• 关键词: Adverse effects; Affect; Alveolar; Antioxidants; Asthma; Child; Childhood; Childhood Asthma; Cholecalciferol; Clinical; Data; Development; Dietary intake; Distal; Dose; Epidemiology; Epithelial; Genetic; Lactation; Lead; Link; Lipids; Lung; Mediating; Mesenchymal; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Pathogenesis; Perinatal; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Play; Predisposition; Pregnancy; Preventive; Rattus; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Supplementation; Therapeutic; Time; Vitamin D; Vitamin D Analog; Vitamin D Deficiency; Vitamins; Wheezing; airway hyperresponsiveness; animal data; base; critical period; design; epidemiologic data; fetal; genetic variant; human data; insight; lung development; lung maturation; mortality; novel; offspring; paracrine; parathyroid hormone-related protein; prevent; protective effect; respiratory; respiratory smooth muscle; surfactant; tool

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.

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 是时空调节围产期肺成熟的局部肺泡旁分泌因子之一。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 会促进围产期肺的成熟，因此维生素 D 的缺乏会以与后代哮喘表型一致的方式扰乱正常的肺结构和功能发育，从而在维生素 D 缺乏和儿童哮喘之间提供了令人信服的机制联系。我们假设妊娠期和围产期维生素 D 缺乏会特异性改变稳态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?) 发育中的肺部信号传导，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。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？导致表面活性剂合成和肺泡间隔增加的信号传导； 2）近端气道平滑肌分化；并检查 3) 怀孕和哺乳期间补充维生素 D 是否可以预防与维生素 D 缺乏相关的形态、结构和功能性肺部变化，从而预防后代患哮喘的倾向。拟议的研究首次严格评估了维生素 D 在围产期肺成熟中的生理作用，并可为补充维生素 D 预防儿童哮喘（儿童发病和死亡的主要原因）的生物学原理和机制基础提供新的理解。这些研究对于确定维生素 D 的最佳剂量至关重要，甚至对于寻找具有最佳呼吸作用且没有任何明显副作用的维生素 D 类似物或代谢物至关重要。此外，由于哮喘既有遗传性又有环境性，这些研究可以为寻找 PTHrP/PPAR? 的遗传变异提供基础。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怀孕期间维生素 D 缺乏与儿童哮喘之间存在联系。然而，这种关联的基本机制尚不清楚。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，而哮喘是儿童发病和死亡的主要原因。