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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：
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.

项目简介: