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：
8307799
负责人：
Jeffrey C Horowitz
金额：
$ 39.13万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307799
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（由申请人提供）：特发性肺纤维化（IPF）是一种纤维化的肺部疾病，其特征是在称为成纤维母细胞簇的下皮下簇内活化的间充质细胞（肌纤维细胞）的积累。这些成纤维细胞灶的丰度与这种疾病的惨淡预后相关，该疾病的中位生存期仅为2 - 3年。没有药理学干预可以改善IPF患者的生存率，并且迫切需要新型有效的疗法来治疗这种疾病。 IPF发病机理涉及对慢性/复发性肺泡上皮损伤的功能失调。肺僵硬增加是肺纤维化的生理相关性，被认为是由肌纤维细胞积累和细胞外基质（ECM）过度沉积引起的。最近的研究称这种纤维发生的范式提出了质疑，表明，组织刚度的增加在肝纤维化中的肌成纤维细胞积累和基质产生之前。这些发现表明，增加的组织刚度可能不是纤维化的简单结果。它可能直接有助于纤维化。然而，先前对肌纤维细胞命运调节的研究重点是使用具有超生理刚度的刚性塑料底物（转化生长因子β-1和内皮蛋白1）的影响。机械转导在肌纤维细胞命运调节中的作用尚不清楚，并且来自ECM的生物力学信号调节了可溶性因子的生化信号来调节成纤维细胞存活/凋亡的作用。局灶性粘附激酶（FAK）是机械转导信号的组成部分，对于维持肌纤维细胞存活至关重要。 FAK在纤维化肺中增加，并抑制FAK衰减小鼠博来霉素诱导的纤维化。此外，纤溶酶介导的ECM蛋白水解诱导肌纤维细胞凋亡，与FAK活性的丧失有关。 FAK在肺纤维化中的核心作用以及在肌纤维细胞存活的调节中，激发了我们的中心假设，即与肺实质僵硬增加相关的机械信号对于间质细胞对凋亡的耐药性至关重要，因此，肺纤维化的病理发生。该建议的具体目的是（1）确定具有生理和病理刚度底物差异调节间充质细胞凋亡的机制；（2）定义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）确定肺依从性，纤维发生和间充质细胞积累之间的关系。拟议的研究将增强我们对生理和病理伤口愈合中肌纤维细胞命运调节的基本理解，并促进鉴定出新型抗纤维化靶标，以干预肺纤维化。