Reorganization of the actin cytoskeleton in airway smooth muscle

气道平滑肌肌动蛋白细胞骨架的重组

基本信息

批准号：
10113413
负责人：
Dale D. Tang
金额：
$ 40.5万
依托单位：
ALBANY MEDICAL COLLEGE
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：
2011-12-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113413
关键词：
Actins Adaptor Signaling Protein Adhesions Affect Allergens Asthma Attenuated Biopsy Biotechnology Cardiovascular system Cell Count Cell Proliferation Cell physiology Cells Confocal Microscopy Cytoskeletal Proteins Cytoskeleton DNA biosynthesis Development Disease EMS1 gene Extrinsic asthma Funding Gene Expression Goals Growth Growth Factor Human Immune In Vitro Janus kinase Knockout Mice Knowledge Laboratories MAPK3 gene Microfilaments Mitogen-Activated Protein Kinases Molecular Muscle Contraction Pathogenesis Pathway interactions Patients Phosphatidylinositols Phosphorylation Phosphotransferases Pilot Projects Platelet-Derived Growth Factor Play Process Property Proteins Research Research Project Grants Role STAT protein STAT3 gene Signal Transduction Signaling Molecule Smooth Muscle Smooth Muscle Myocytes Stimulus Testing Thick Total Internal Reflection Fluorescent airway hyperresponsiveness asthma exacerbation asthmatic asthmatic airway smooth muscle cell motility experimental study in vivo knock-down member migration novel novel therapeutics polymerization profilin 1 respiratory smooth muscle response spatiotemporal spectrin SH3 domain binding protein 1 tool vasodilator-stimulated phosphoprotein

项目摘要

Airway smooth muscle cell proliferation plays an important role in the pathogenesis of airway smooth muscle layer thickening, cardinal features of asthma that affects nearly 250 million people worldwide. In addition, bronchial biopsy of patients with severe asthma suggests that airway smooth muscle migration contributes to smooth muscle thickening in the airways. The mechanisms that regulate smooth muscle cell proliferation and migration are not fully elucidated. Abi1 (Abl interactor 1) is an adapter protein that has a role in actin cytoskeletal remodeling in nonmuscle cells and smooth muscle contraction. Nevertheless, the role and mechanisms of Abi1 in smooth muscle cell proliferation and migration have not been previously investigated. Pilot studies have shown that Abi1 knockdown attenuates DNA synthesis and cell numbers enhanced by platelet-derived growth factor (PDGF), suggesting an important role of Abi1 in regulating airway smooth muscle cell proliferation. In Aim 1, the role of Abi1 in regulating the Jak2 and STAT3 phosphorylation, and other pathways will be evaluated in cells upon stimulation with growth factors. In Aim 2, the role of Abi1 in airway smooth muscle migration and its effectors will be evaluated. In Aim 3, the role of Abi1 in allergen- induced airway smooth muscle thickening will be evaluated by using conditional Abi1 knockout mice. Moreover, the potential role of Abi1-associated pathways in human asthma will be determined. Completion of these studies should advance our knowledge regarding functional role and mechanism of the adapter protein Abi1 in smooth muscle cell proliferation and migration in vitro, and asthma pathogenesis in vivo. Obtaining this knowledge will facilitate the development of new therapy to treat asthma.

气道平滑肌细胞增殖在气道平滑肌层增厚的发病机制，哮喘的基本特征全世界影响近2.5亿人。此外，患者的支气管活检严重的哮喘表明气道平滑肌迁移有助于平滑气道中的肌肉增厚。调节平滑肌细胞的机制增殖和迁移并未完全阐明。 ABI1（ABL交互器1）是一个适配器蛋白质在非肌肉细胞中具有肌动蛋白细胞骨架重塑和光滑的蛋白质肌肉收缩。然而，ABI1在平滑肌中的作用和机制先前尚未研究细胞增殖和迁移。试点研究表明ABI1敲低会减弱DNA的合成和细胞数量。血小板衍生的生长因子（PDGF），这表明ABI1在调节中的重要作用气道平滑肌细胞增殖。在AIM 1中，ABI1在调节JAK2中的作用 STAT3磷酸化以及其他途径将在细胞中评估刺激生长因子。在AIM 2中，ABI1在气道平滑肌中的作用将评估迁移及其效应子。在AIM 3中，ABI1在过敏原中的作用通过使用条件ABI1评估诱导的气道平滑肌增厚淘汰老鼠。此外，与ABI1相关途径在人类中的潜在作用将确定哮喘。这些研究的完成应该提高我们的知识关于平滑肌中适配器蛋白ABI1的功能作用和机制体外细胞增殖和迁移，体内哮喘发病机理。获得这个知识将有助于开发新疗法以治疗哮喘。