Regulation of airway smooth muscle phenotype by retinoic acid

视黄酸对气道平滑肌表型的调节

基本信息

批准号：
9124071
负责人：
FELICIA CHEN
金额：
$ 43.08万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-20 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9124071
关键词：
Adult Affect Animals Asthma Atomic Force Microscopy Attenuated Biochemical Bioinformatics Biological Assay Cell Culture Techniques Cell Size Complex Data Disease Functional disorder Generations Genes Genetic Models Genetic Polymorphism Health Histologic Homeostasis Human In Vitro Individual Life Link Literature Lung Maintenance Measurement Measures Mediating Messenger RNA Molecular Mus Muscle Muscle Development Muscle function Obstruction Pathogenesis Pathway interactions Phenotype Physiological Play Population Preparation Property Public Health RARB gene Receptor Gene Regulation Retinoic Acid Receptor Role Serum Shortness of Breath Signal Transduction Slice Smooth Muscle Myocytes Stimulus Structure Testing Thick Tissues Traction Transforming Growth Factor beta Transgenic Model Translating Tretinoin Vitamin A Vitamin A Deficiency Work airway hyperresponsiveness airway inflammation base cellular targeting constriction data modeling genome wide association study in vivo in vivo Model insight mathematical model morphogens muscle form novel postnatal prenatal public health relevance receptor respiratory smooth muscle

项目摘要

DESCRIPTION (provided by applicant): Asthma is characterized by airflow limitation and airway hyperresponsiveness (AHR). Airway smooth muscle (ASM), the primary effector of airway tone and responsiveness to constricting stimuli, therefore, is important to the pathogenesis of asthma. Experimental data and mathematical models indicate that ASM plays a central role in the pathogenesis of asthma by undergoing marked phenotypic changes, including the acquisition of a hypercontractile and hyperresponsive state. However, the precise molecular signals governing these changes in vivo is incompletely understood. We now have evidence that inhibition of retinoic acid (RA), the active metabolite of vitamin A, in adult mice for only fve days results in a significant increase in AHR and ASM mass without evidence of airway inflammation. Based on our preliminary findings and the emerging literature linking vitamin A to the maintenance of airway health in humans, we hypothesize that ongoing RA signaling in the adult airway is required to maintain normal airway health by regulating ASM phenotype. To test our hypothesis, we will identify the changes in airway structure and function in the setting of RA deficiency by using histologic, biochemical, and physiologic assays in live animals, freshly-isolated lungs, and precision-cut lung slices. We will establish whether RA signaling in ASM is mediated through its receptor RARβ in vivo. In addition, we will examine the influences of RA on the physical and molecular properties of ASM using freshly isolated mouse ASMs and human ASMs collected from donor lungs. Finally, we will investigate the regulation of TGFβ signaling in ASM by RA in vivo. At the end of this project, we will establish a functional link between vitamin A and airway homeostasis, deepen our understanding of the cellular, physical, and molecular features of ASM, and provide novel information on genes and pathways in the pathogenesis of diseases characterized by airflow obstruction.

描述（由申请人提供）：哮喘的特征是气流受限和气道高反应性（AHR），气道平滑肌（ASM）是气道张力和对收缩刺激的反应的主要效应器，因此对于哮喘的发病机制很重要。数据和数学模型表明，ASM 通过经历显着的表型变化，包括获得过度收缩和然而，体内控制这些变化的精确分子信号尚不完全清楚，我们现在有证据表明，在成年小鼠中，抑制维生素A的活性代谢物维甲酸（RA）仅五天就会导致显着增加。根据我们的初步研究结果和将维生素 A 与维持人类气道健康联系起来的新兴文献，我们发现成人气道中持续的 RA 信号传导是维持正常气道所必需的。为了检验我们的假设，我们将通过对活体动物、新鲜分离的肺和精确切割的肺进行组织学、生化和生理测定来确定 RA 缺陷情况下气道结构和功能的变化。我们将确定 ASM 中的 RA 信号传导是否是通过其体内受体 RARβ 介导的。此外，我们将使用新鲜分离的小鼠 ASM 和人类来研究 RA 对 ASM 物理和分子特性的影响。最后，我们将通过体内 RA 对 ASM 中 TGFβ 信号的调节，建立维生素 A 和气道稳态之间的功能联系，加深我们对细胞、物理的理解。和 ASM 的分子特征，并提供有关以气流阻塞为特征的疾病发病机制中的基因和途径的新信息。