Cytoskeletal Regulation of Airway Smooth Muscle

气道平滑肌的细胞骨架调节

基本信息

批准号：
8273438
负责人：
Dale D. Tang
金额：
$ 35.55万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8273438
关键词：
ABL1 gene Actins Adhesions Affect Allergens Animal Model Antibodies Asthma Attenuated Biological Blood Vessels Cell Proliferation Cell physiology Cells Coomassie blue Cytoskeletal Proteins Cytoskeleton Development Disease Endocytosis Epidermal Growth Factor Fibroblasts Goals Growth Growth Factor Human Immunoblot Analysis In Vitro Knockout Mice Knowledge Laboratories Lung diseases Mediating Methods Microfilaments Mitogen-Activated Protein Kinases Mucous body substance Muscle Contraction Muscle function Pathogenesis Pathology Pathway interactions Phosphorylation Pilot Projects Platelet-Derived Growth Factor Play Protein Tyrosine Kinase Proteins Reagent Regulation Research Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Staining method Stains Technology Testing Tissues adapter protein airway hyperresponsiveness airway inflammation airway remodeling c-abl Proto-Oncogenes cell growth human EMS1 protein immune function in vivo migration polymerization prevent respiratory smooth muscle response tool

项目摘要

DESCRIPTION (provided by applicant): Asthma is a serious pulmonary disease that is characterized by airway hyper-responsiveness (AHR), airway remodeling, mucus hyper-secretion and airway inflammation. There is considerable information about the pathogenesis of mucus hyper-secretion and airway inflammation. Our knowledge regarding mechanisms of AHR and airway remodeling is limited. Previous studies show that contraction of airway smooth muscle plays a critical role in mediating AHR whereas proliferation of airway smooth muscle cells largely contributes to the pathogenesis of airway remodeling. However, the mechanisms that regulate airway smooth muscle contraction and growth are not well understood. Abl is a nonreceptor tyrosine kinase that is known to regulate the functions of immune cells by controlling actin polymerization, a cellular process that may also regulate contraction of various smooth muscles including airway smooth muscle. Our pilot studies show that Abl is required for airway smooth muscle contraction and growth, suggesting an important role of Abl in airway smooth muscle. The major goal of the project is to characterize the functional role of Abl in airway smooth muscle in vitro and in allergen-induced AHR and airway remodeling in vivo. In Aims 1 and 2, the roles and mechanisms of Abl in regulating airway smooth muscle contraction and growth will be characterized. In Aim 3, the roles of Abl in allergen-induced AHR, airway remodeling and inflammation will be evaluated using an animal model of asthma. Completion of these studies should advance our knowledge regarding smooth muscle contraction/growth and asthma pathology. Obtaining this knowledge may identify Abl as a new biological target for the development of new therapy to treat asthma. PUBLIC HEALTH RELEVANCE: Airway smooth muscle contraction and growth play a critical role in the pathogenesis of airway hyper-responsiveness and airway remodeling. However, the mechanisms that regulate smooth muscle contraction and growth are not well understood. This project is to unveil previously unknown mechanisms that control airway smooth muscle contraction and proliferation using sophisticated technology. Obtaining this knowledge is necessary for the development of new strategies to prevent/treat the disease.

描述（由申请人提供）：哮喘是一种严重的肺部疾病，其特征是气道高反应性（AHR）、气道重塑、粘液过度分泌和气道炎症。关于粘液过度分泌和气道炎症的发病机制有大量信息。我们对 AHR 和气道重塑机制的了解有限。先前的研究表明，气道平滑肌的收缩在介导 AHR 中发挥着关键作用，而气道平滑肌细胞的增殖在很大程度上促进了气道重塑的发病机制。然而，调节气道平滑肌收缩和生长的机制尚不清楚。 Abl 是一种非受体酪氨酸激酶，已知可以通过控制肌动蛋白聚合来调节免疫细胞的功能，肌动蛋白聚合是一种细胞过程，也可以调节包括气道平滑肌在内的各种平滑肌的收缩。我们的初步研究表明，Abl 是气道平滑肌收缩和生长所必需的，这表明 Abl 在气道平滑肌中发挥着重要作用。该项目的主要目标是表征 Abl 在体外气道平滑肌中以及在体内过敏原诱导的 AHR 和气道重塑中的功能作用。在目标 1 和 2 中，将描述 Abl 在调节气道平滑肌收缩和生长中的作用和机制。在目标 3 中，将使用哮喘动物模型评估 Abl 在过敏原诱导的 AHR、气道重塑和炎症中的作用。完成这些研究应该会增进我们对平滑肌收缩/生长和哮喘病理学的了解。获得这一知识可能会将 Abl 确定为开发治疗哮喘新疗法的新生物靶点。公共卫生相关性：气道平滑肌收缩和生长在气道高反应性和气道重塑的发病机制中发挥着关键作用。然而，调节平滑肌收缩和生长的机制尚不清楚。该项目旨在揭示以前未知的机制，利用先进的技术控制气道平滑肌收缩和增殖。获得这些知识对于制定预防/治疗该疾病的新策略是必要的。