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

基本信息

批准号：
8298583
负责人：
VIRENDER K REHAN
金额：
$ 16.79万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298583
关键词：
Adverse effects Affect Alveolar Antioxidants Asthma Child Childhood Childhood Asthma Cholecalciferol Clinical Data Development Diet 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

项目摘要

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.

描述（由申请人提供）：有很强的流行病学数据表明，怀孕期间和儿童哮喘的维生素D缺乏之间存在联系。此外，有强大的实验性动物数据表明，维生素D是空间临时调节围产期肺部成熟的局部肺泡旁氨基因子之一。但是，尚不清楚怀孕和儿童哮喘期间维生素D缺乏症之间的机械联系。我们的初步数据表明，维生素D增强了围产期肺部成熟，使其缺乏会以与后代哮喘表型相一致的方式扰动正常的肺结构和功能发育，从而提供了令人信服的机械性与维生素D缺乏症和童年哮喘之间的强迫机械联系。我们假设怀孕期间的维生素D缺乏症特异性地改变了稳态甲状旁腺相关蛋白/过氧化物酶体增殖物激活的受体吗？（PTHRP/PPAR？）发育中的肺信号传导，导致近端和远端气道的肌源性表型增强，并在怀孕期间补充足够的维生素D会阻塞后代的哮喘的发展。使用维生素D缺乏症和最先进的分子工具的大鼠模型，我们将确定维生素D在促进促进的作用1）PTHRP/PPAR介导的肺泡上皮 - 间质相互作用？信号导致表面活性剂合成和肺泡分离增加； 2）气道近端平滑肌分化； 3）是否在怀孕和泌乳期间补充维生素D是否会防止与维生素D缺乏相关的形态，结构和功能性肺变化，从而导致后代哮喘的倾向。提出的研究首次批判性地评估了维生素D在围产期肺部成熟中的生理作用，并可以为生物学理由和机械基础提供新颖的理解，以防止儿童哮喘，这是对儿童哮喘的主要贡献，是儿童死亡率的主要贡献。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，以找到具有最佳呼吸作用的维生素D类似物或代谢物，而没有任何显着的副作用。此外，由于哮喘的起源既是遗传和环境，因此这些研究可以提供基础，以找到PTHRP/PPAR中的遗传变异？以及确定维生素D对儿童哮喘影响的WNT信号通路。