Mechanobiology of Lung Fibrosis

肺纤维化的力学生物学

基本信息

批准号：
9187038
负责人：
Daniel J. Tschumperlin
金额：
$ 40.53万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-06 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187038
关键词：
Actins Address Adoptive Transfer Apoptosis Attenuated Automobile Driving Biochemical Biological Models Biology Bleomycin Cell Cycle Cell Nucleus Cell physiology Cell-Matrix Junction Cells Clinical Collagen Cues Data Deposition Disease Doxycycline Environment Extracellular Matrix Fibroblasts Fibrosis Focal Adhesions Gases Gene Expression Generations Heart Human In Vitro Kidney Knowledge Lead Link Liver Lung Mechanics Mediating Mediator of activation protein Mesenchymal Modeling Molecular Morphology Mus Nuclear Nuclear Matrix Organ Organ Size Pathogenicity Pathologic Pathway interactions Patients Pharmacology Physiological Process Proteins Pulmonary Fibrosis RNA Interference Resistance Role Signal Transduction Skin Slice Small Interfering RNA Stem cells Stimulus Structure of parenchyma of lung Testing Tissue Model Tissues Traction Transcript Transcription Coactivator Transfection Transforming Growth Factor beta Translating Work base end stage disease experimental study gain of function human disease human tissue insight knock-down leupaxin loss of function mouse model mutant novel outcome forecast overexpression paxillin public health relevance receptor response soft tissue targeted treatment therapeutic development therapy development

项目摘要

DESCRIPTION (provided by applicant): Fibrosis is a pathobiological process common to many tissues and diseases which results in tissue remodeling and loss of function, often necessitating organ replacement or leading to end-stage disease. No therapies are currently available that successfully arrest or reverse fibrosis, and this represents a significant unmet clinical need. Fibrosis occurs predominantly in soft tissues (lung, liver, kidney, heart, skin) through excess fibroblast activation to a contractile/proliferative/apoptosis resistant state and accompanying deposition of extracellular matrix. We have discovered that fibroblasts are exquisitely sensitive to alterations in matrix stiffness; this finding is true for both normal and disease-derived fibroblasts, and spans the stiffness range found in normal and fibrotic lung tissue. In this project, we seek to dissect a novel molecular pathway linking matrix stiffness to fibroblast activation, and test whether this pathway is relevant in human fibrosis and essential in driving fibrosis in model systems. We focus on the transcriptional co-activators YAP and TAZ, evolutionarily conserved regulators of organ size, cell cycle, and stem cell function. Our preliminary data demonstrate enhanced nuclear localization of YAP/TAZ in human IPF tissue, and strongly support an essential role for YAP and TAZ in fibroblast activation downstream of both matrix stiffness and TGF-beta, two pivotal regulators of fibroblast biology. We hypothesize that YAP and TAZ are mechanically activated regulators of lung fibrosis that coordinate and integrate fibroblast matrix stiffness and biochemical responses leading to a cascade of pro-fibrotic functions that drive progressive fibrosis. We will evaluate this hypothesis in two aims using in vitro, mouse and human tissue models relevant to human disease. The proposed studies will advance the field by elucidating a novel point of convergence linking mechanical and biochemical cues to fibroblast activation and pulmonary fibrosis. If successful, the proposed studies could lead to new avenues for development of therapies targeting YAP and TAZ in fibrosis of the lung and other soft tissues.

描述（由申请人提供）：纤维化是许多组织和疾病常见的病理生物学过程，导致组织重塑和功能丧失，通常需要器官置换或导致终末期疾病。目前还没有可以成功阻止或逆转纤维化的疗法，这代表了一个重大的未满足的临床需求。纤维化主要发生在软组织（肺、肝、肾、心脏、皮肤）中，通过过度的成纤维细胞激活至收缩/增殖/凋亡抵抗状态并伴随细胞外基质的沉积。我们发现成纤维细胞对基质硬度的变化极其敏感。这一发现对于正常和疾病来源的成纤维细胞都是正确的，并且跨越了正常和纤维化肺组织中发现的硬度范围。在这个项目中，我们试图剖析一种将基质刚度与成纤维细胞活化联系起来的新分子途径，并测试该途径是否与人类纤维化相关以及是否对人类纤维化至关重要。驱动模型系统纤维化。我们重点关注转录共激活因子 YAP 和 TAZ，它们是器官大小、细胞周期和干细胞功能的进化保守调节因子。我们的初步数据表明，YAP/TAZ 在人 IPF 组织中的核定位增强，并强烈支持 YAP 和 TAZ 在基质硬度和 TGF-β（成纤维细胞生物学的两个关键调节因子）下游的成纤维细胞激活中发挥重要作用。我们假设 YAP 和 TAZ 是机械激活的肺纤维化调节剂，协调和整合成纤维细胞基质硬度和生化反应，导致一系列促纤维化功能，驱动进行性纤维化。我们将使用与人类疾病相关的体外小鼠和人体组织模型在两个目标上评估这一假设。拟议的研究将通过阐明将机械和生化线索与成纤维细胞活化和肺纤维化联系起来的新聚合点来推进该领域的发展。如果成功，拟议的研究可能会为开发针对肺和其他软组织纤维化的 YAP 和 TAZ 疗法提供新途径。