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（由适用提供）：哮喘的特征是气流限制和气道高应答（AHR）。气道平滑肌（ASM），因此气道音调的主要效果和对刺激的反应性对哮喘的发病机理很重要。实验数据和数学模型表明，ASM通过经历明显的表型变化（包括获取超额合同和超响应状态）在哮喘的发病机理中起着核心作用。然而，尚不完全理解管理体内这些变化的精确分子信号。现在，我们有证据表明，在成年小鼠中抑制视黄酸（RA），即维生素A的活性代谢产物，仅FVE天就导致AHR和ASM质量显着增加，而没有气道感染的证据。根据我们的初步发现以及将维生素A与人类气道健康联系起来的新兴文献，我们假设成人气道中的RA信号传导是通过反思ASM表型来维持正常气道健康的。为了检验我们的假设，我们将通过在活体动物，新鲜分离的肺以及精确切割的肺切片中使用组织学，生化和生理测定方法来确定RA缺乏症中气道结构和功能的变化。我们将确定ASM中的RA信号是否通过其体内受体RARβ介导。此外，我们将使用新鲜分离的小鼠ASM和从供体肺中收集的新型小鼠ASM和人类ASM来检查RA对ASM物理和分子特性的影响。最后，我们将通过RA IN VIVO研究ASM中TGFβ信号传导的调节。在该项目的结尾，我们将建立维生素A与气道体内稳态之间的功能联系，加深我们对ASM的细胞，物理和分子特征的理解，并提供有关气流反对表征的疾病发病机理的基因和途径的新信息。