Elucidating tensin1-associated signals that promote fibronectin matrix assembly and lung fibrosis

阐明促进纤连蛋白基质组装和肺纤维化的张力蛋白1相关信号

基本信息

批准号：
9899303
负责人：
NATHAN K SANDBO
金额：
$ 34.43万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899303
关键词：
Adhesions Adhesives Back Binding Bleomycin Cell Culture Techniques Cell Lineage Cells Cessation of life Cicatrix Clinical Complex Cues Deposition Development Diagnosis Disease Disease Progression Etiology Event Extracellular Matrix FDA approved Fibroblasts Fibronectins Fibrosis Focal Adhesion Kinase 1 Focal Adhesions Gap Junctions Gases Genes Goals Human Individual Injury Integrins Intervention Investigation Knowledge Lead Lung Mediating Modeling Molecular Morbidity - disease rate Mus Myofibroblast Pathway interactions Patient Care Patients Physicians Play Primary Cell Cultures Process Proteins Pulmonary Fibrosis Research Research Proposals Respiratory physiology Role Scientist Signal Pathway Signal Transduction Single Nucleotide Polymorphism Structure of parenchyma of lung Testing Therapeutic Tissues Work fibrogenesis functional decline human disease idiopathic pulmonary fibrosis in vitro Model in vivo in vivo Model injury and repair integrin-linked kinase mortality new therapeutic target novel strategies programs pulmonary function decline repaired response response to injury rho rho GTP-Binding Proteins scaffold tensin wound healing

项目摘要

Project Abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by unrelenting scarring and stiffening of the lungs that leads to death within 3-4 years after diagnosis. As IPF kills 40,000 individuals in the U.S. each year, new treatments are urgently needed to abrupt the progression of this disease. We have found that the focal adhesion gene, tensin (TNS1), plays a role in myofibroblast differentiation, the formation of new extracellular matrix (ECM), and the progression of pulmonary fibrosis. However, it is not known how TNS1 mediates matrix remodeling and lung function decline. Our rationale is that determining the role of TNS1 in myofibroblast differentiation and development of pulmonary fibrosis will allow us to directly target new ECM formation, thus disrupting progression of the disease. We hypothesize that TNS1 cooperates with focal adhesion kinase (FAK) and Rho-dependent signals to induce myofibroblast differentiation and pulmonary fibrosis in vivo. To test this hypothesis, we will: Aim 1. Determine how TNS1 modifies the reparative response to injury in vivo. Key findings in human disease and in vitro models suggest a key role for TNS1 in matrix assembly and the progression of pulmonary fibrosis. In this aim, we will determine how TNS1 modifies the in vivo reparative response to injury. To do so, we will utilize conditional deletion of TNS1 in an in vivo model of injury/repair (bleomycin model) to determine how TNS1-associated signaling modifies early injury responses, global reparative response, and cell fate determination during repair. Aim 2. Determine cooperative signaling used by TNS1 to promote fibronectin matrix assembly and myofibroblast differentiation. We hypothesize that TNS1 may cooperate with Rho and FAK to modify cell fate, and integrin-linked kinase signaling to facilitate fibronectin (FN) matrix assembly. To elucidate the pathways involved in FN matrix assembly, we will utilize human lung primary cell cultures and murine cell cultures from TNS1f,f mice to determine how TNS1 localizes to adhesive complexes, modifies Rho, ILK, and FAK signaling, and facilitates fibrillar adhesion formation, FN fibril assembly, and ECM deposition. Upon completion of these studies, we will have determined key signaling events in modifying the reparative response to injury and key signaling pathways that modify FN matrix assembly. This knowledge will provide targets for intervention to disrupt cell-mediated matrix formation, thereby expanding our therapeutic options to halt pulmonary fibrosis in vivo. As a physician-scientist who is both dedicated to the care of patients with pulmonary fibrosis and has a track-record of productive investigation of mechanisms mediating myofibroblast development, matrix assembly, and in vivo fibrosis, I am well-poised to lead this study and bring this work to completion.

项目摘要：特发性肺纤维化 (IPF) 的特点是肺部不断形成疤痕和僵硬，导致确诊后3-4年内死亡。在美国，IPF 每年导致 40,000 人死亡，新的治疗方法迫切需要阻止这种疾病的进展。我们发现粘着斑基因，张力蛋白 (TNS1) 在肌成纤维细胞分化、新细胞外基质 (ECM) 的形成和肺纤维化的进展。然而，目前尚不清楚TNS1如何介导基质重塑和肺功能衰退。我们的基本原理是确定 TNS1 在肌成纤维细胞分化和肺纤维化的发展将使我们能够直接针对新的 ECM 形成，从而破坏进展的疾病。我们假设 TNS1 与粘着斑激酶 (FAK) 和 Rho 依赖性蛋白协同作用体内诱导肌成纤维细胞分化和肺纤维化的信号。为了检验这个假设，我们将：目标 1. 确定 TNS1 如何改变体内损伤的修复反应。人类的主要发现疾病和体外模型表明 TNS1 在基质组装和肺疾病进展中发挥关键作用纤维化。为此，我们将确定 TNS1 如何改变体内对损伤的修复反应。为此，我们将在体内损伤/修复模型（博莱霉素模型）中利用 TNS1 的条件删除来确定 TNS1 相关信号如何改变早期损伤反应、整体修复反应和细胞命运修复时的测定。目标 2. 确定 TNS1 用于促进纤连蛋白基质组装和肌成纤维细胞分化。我们假设TNS1可能与Rho和FAK合作来改变细胞命运，整合素连接激酶信号传导促进纤连蛋白 (FN) 基质组装。阐明途径参与 FN 基质组装，我们将利用人肺原代细胞培养物和小鼠细胞培养物 TNS1f,f 小鼠以确定 TNS1 如何定位于粘附复合物、修改 Rho、ILK 和 FAK 信号传导，并促进原纤维粘附形成、FN 原纤维组装和 ECM 沉积。完成这些研究后，我们将确定修复修复过程中的关键信号事件对损伤的反应和修改 FN 基质组装的关键信号通路。这些知识将提供干扰细胞介导的基质形成的干预目标，从而扩大我们的治疗选择阻止体内肺纤维化。作为一名致力于护理患者的医师兼科学家肺纤维化，并对介导肌成纤维细胞的机制具有富有成效的研究记录发育、基质组装和体内纤维化，我已经准备好领导这项研究并将这项工作带到完成。