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Mesenchymal Cell Fate Determination by Extracellular Matrix Stiffness

通过细胞外基质硬度确定间充质细胞的命运

基本信息

批准号：
8874259
负责人：
Jeffrey C Horowitz
金额：
$ 38.56万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2011-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874259
关键词：
Active Sites Alveolar Apoptosis Apoptotic Appearance Attenuated Biochemical Biomechanics Bleomycin Cell Survival Cells Characteristics Chronic Chronic Disease Clinical Cues Deposition Dinoprostone Disease Employee Strikes Endothelin-1 Epithelial Epithelial Cells Extracellular Matrix Fibroblasts Fibrosis Focal Adhesion Kinase 1 Hamman-Rich syndrome In Vitro Injury Intervention Liver Fibrosis Lung Lung Compliance Lung diseases Maintenance Mechanics Mediating Mediator of activation protein Mesenchymal Modeling Mus Myofibroblast Outcome Pathogenesis Pathologic Pathologic Processes Pathway interactions Patients Phenotype Phosphotransferases Physical environment Physiological Plasmin Plastics Production Property Proteolysis Pulmonary Fibrosis Recurrence Regulation Resistance Resolution Role Severities Signal Transduction Stimulus Structure of parenchyma of lung Tissues Wound Healing behavior influence cell behavior effective therapy fibrogenesis human TGFB1 protein improved in vivo injured mortality novel novel strategies outcome forecast physical property repaired response

项目摘要

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a fibrotic lung disease characterized by the accumulation of activated mesenchymal cells (myofibroblasts) within subepithelial clusters called fibroblastic foci. The abundance of these fibroblastic foci correlates with the dismal prognosis of this disease, which has a median survival of only 2-3 years. No pharmacologic intervention has improved survival for patients with IPF, and there is an urgent need for novel and efficacious therapies to treat this disease. IPF pathogenesis involves a dysfunctional response to chronic/recurrent alveolar epithelial injury. Increased lung stiffness is a physiologic correlate of pulmonary fibrosis that has been thought to result from myofibroblast accumulation and excessive deposition of extracellular matrix (ECM). Calling this paradigm of fibrogenesis into question, recent studies show that increased tissue stiffness precedes myofibroblast accumulation and matrix production in liver fibrosis. These findings suggest that increased tissue stiffness may not be a simple consequence of fibrosis; it may directly contribute to fibrogenesis. Prior studies of the myofibroblast fate regulation, however, have focused on the effects of soluble mediators (transforming growth factor beta-1 and endothelin-1), using rigid plastic substrates with supra-physiologic stiffness. The role of mechanotransduction in the regulation of myofibroblast fate is not known, and the mechanisms by which biomechanical signals from the ECM modulate biochemical signals from soluble factors to regulate fibroblast survival/apoptosis are poorly understood. Focal adhesion kinase (FAK) is an integral component of mechanotransduction signaling that is critical for the maintenance of myofibroblast survival. FAK is increased in fibrotic lungs, and inhibition of FAK attenuates bleomycin-induced fibrosis in mice. Moreover, plasmin-mediated ECM proteolysis, which induces myofibroblast apoptosis, is associated with the loss of FAK activity. The central role of FAK in pulmonary fibrosis and in the regulation of myofibroblast survival motivates our central hypothesis that mechanical signals associated with increased lung parenchymal stiffness are critical for mesenchymal cell resistance to apoptosis and, therefore, the pathogenesis of pulmonary fibrosis. The specific aims of this proposal are to (1) determine the mechanisms by which substrates with physiologic and pathologic stiffness differentially regulate mesenchymal cell apoptosis; (2) define how mechanical stimuli modulate the effects of soluble mediators on mesenchymal cell apoptosis; and (3) determine the relationship between lung compliance, fibrogenesis, and mesenchymal cell accumulation. The proposed studies will enhance our fundamental understanding of myofibroblast fate regulation in physiologic and pathologic wound healing and facilitate identification of novel anti-fibrotic targets for intervention in pulmonary fibrosis.

描述（由申请方提供）：特发性肺纤维化（IPF）是一种纤维化肺病，其特征为活化的间充质细胞（肌成纤维细胞）在称为成纤维细胞灶的上皮下簇内蓄积。这些成纤维细胞灶的丰富与这种疾病的预后不良相关，其中位生存期仅为2-3年。没有任何药物干预改善了IPF患者的生存率，因此迫切需要新的有效疗法来治疗这种疾病。 IPF发病机制涉及对慢性/复发性肺泡上皮损伤的功能障碍性反应。肺硬度增加是肺纤维化的生理相关性，其被认为是由肌成纤维细胞积聚和细胞外基质（ECM）过度沉积引起的。最近的研究表明，肝纤维化中组织硬度的增加先于肌成纤维细胞的积累和基质的产生。这些发现表明，组织硬度增加可能不是纤维化的简单结果;它可能直接导致纤维化。然而，以前的肌成纤维细胞命运调控的研究集中在可溶性介质（转化生长因子β-1和内皮素-1）的影响，使用具有超生理刚度的硬质塑料基板。机械传导在调节肌成纤维细胞命运中的作用尚不清楚，并且来自ECM的生物力学信号调节来自可溶性因子的生化信号以调节成纤维细胞存活/凋亡的机制也知之甚少。粘着斑激酶（FAK）是维持肌成纤维细胞存活的关键机械转导信号的组成部分。FAK在纤维化肺中增加，并且FAK的抑制减弱了小鼠中博来霉素诱导的纤维化。此外，纤溶酶介导的ECM蛋白水解，诱导肌成纤维细胞凋亡，与FAK活性的丧失。FAK在肺纤维化和肌成纤维细胞存活调节中的中心作用激发了我们的中心假设，即与肺实质硬度增加相关的机械信号对于间充质细胞抗凋亡至关重要，因此，肺纤维化的发病机制。本提案的具体目的是（1）确定生理和病理硬度基质差异调节间充质细胞凋亡的机制;（2）确定机械刺激如何调节可溶性介质对间充质细胞凋亡的影响;（3）确定肺顺应性、纤维化和间充质细胞蓄积之间的关系。拟议的研究将增强我们对生理和病理伤口愈合中肌成纤维细胞命运调控的基本理解，并促进识别用于干预肺纤维化的新型抗纤维化靶点。