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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：
10589038
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589038
关键词：
Acceleration Adhesions Adhesives Back Binding Bleomycin Cell Culture Techniques Cell Lineage Cells Cessation of life Cicatrix Clinical Complex Cues Dedications Deposition Development Diagnosis Disease Disease Progression Etiology Event Extracellular Matrix Extracellular Matrix Proteins FDA approved Fibroblasts Fibronectins Fibrosis Focal Adhesion Kinase 1 Focal Adhesions Gases General Population 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 Productivity Proteins Pulmonary Fibrosis Research Research Proposals 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 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）的特征是持续的瘢痕形成和肺硬化，在确诊后3-4年内死亡。由于IPF每年在美国导致40，000人死亡，我们迫切需要阻止这种疾病的发展。我们发现黏着斑基因，张力蛋白（TNS 1）在肌成纤维细胞分化、新的细胞外基质（ECM）的形成和肺纤维化的进展。然而，目前尚不清楚TNS 1如何介导基质重塑和肺损伤。功能衰退。我们的基本原理是，确定TNS 1在肌成纤维细胞分化中的作用，肺纤维化的发展将使我们能够直接靶向新的ECM形成，从而破坏进展的疾病。我们假设TNS 1与黏着斑激酶（FAK）和Rho依赖性的信号以诱导体内肌成纤维细胞分化和肺纤维化。为了验证这个假设，我们将：目标1.确定TNS 1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TNS 1在基质组装和肺肿瘤进展中起关键作用，纤维化在这个目标中，我们将确定TNS 1如何修改体内损伤的修复反应。要执行此操作，我们将在损伤/修复的体内模型（博来霉素模型）中利用TNS 1的条件性缺失来确定 TNS 1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过程中的判断。目标二。确定TNS 1用于促进纤连蛋白基质组装的协同信号传导，肌成纤维细胞分化我们推测TNS 1可能与Rho和FAK合作改变细胞命运，和整合素连接的激酶信号传导以促进纤连蛋白（FN）基质组装。为了阐明参与FN基质组装，我们将利用人肺原代细胞培养物和来自 TNS 1f，f小鼠以确定TNS 1如何定位于粘附复合物，修饰Rho、ILK和FAK信号传导，并促进纤维粘附形成、FN纤维组装和ECM沉积。在完成这些研究后，我们将确定在修饰修复性细胞中的关键信号事件。对损伤的反应和修饰FN基质组装的关键信号通路。这些知识将提供靶点干预破坏细胞介导的基质形成，从而扩大我们的治疗选择，阻止体内肺纤维化。作为一名医生兼科学家，他既致力于照顾病人，肺纤维化，并有一个跟踪记录的机制介导肌成纤维细胞的生产性研究开发，矩阵组装和体内纤维化，我准备好领导这项研究，并把这项工作，建成