TGF-beta, matrix, and myofibroblasts in hepatic fibrosis

肝纤维化中的 TGF-β、基质和肌成纤维细胞

• 批准号: 7908387
• 负责人: REBECCA G WELLS
• 金额: $ 10万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908387
• 关键词: Address; Adhesions; Affect; Arts; Cells; Cessation of life; Chronic; Cirrhosis; Cytoskeleton; Data; Diagnosis; Enzymes; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Figs - dietary; Goals; Growth Factor; Hepatic; Hepatic Stellate Cell; In Vitro; Integrins; LOX gene; Literature; Liver; Liver Fibrosis; Liver diseases; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Myofibroblast; Pathway interactions; Phenotype; Population; Process; Property; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Smooth Muscle Actin Staining Method; Stress Fibers; Time; Tissues; Transforming Growth Factor beta; United States; Work; cell type; crosslink; in vivo; novel strategies; regional difference; research study; transdifferentiation

DESCRIPTION (provided by applicant): Liver fibrosis and cirrhosis are the end result of chronic liver disease from multiple causes, affecting 400,000 people and resulting in more than 20,000 deaths in the United States annually. Fibrosis occurs at the cellular level when a variety of cell types activate to fibrogenic, alpha-smooth muscle actin (alpha-SMA)- expressing myofibroblasts. In the liver, hepatic stellate cells (HSC) and portal fibroblasts (PF) are considered the two most important cell types to undergo activation. Factors mediating the activation of HSC and PF are poorly understood in spite of a decade of intensive study. We have studied the process of HSC activation in vitro, and have proposed a preliminary two-step model in which the myofibroblast phenotype results from an interplay between mechanical and soluble factors. In this model, HSC express alpha-SMA when subjected to mechanical tension from the extracellular matrix (ECM) and then, under the influence of TGF-beta signaling via the cytoplasmic signaling intermediate SmadS, organize the alpha-SMA into stress fibers, becoming fully activated myofibroblasts. The goal of this proposal is to develop a detailed understanding of the role of mechanical factors (adhesion-dependent mechanical tension) in hepatic myofibroblast activation in vitro and in vivo. Our hypothesis is that the mechanical properties of the ECM in the context of TGF-beta signaling are critical for the activation of HSC and PF to myofibroblasts in fibrosis. We propose to address this goal and hypothesis through three specific aims: 1) To determine the role of integrins and downstream signal transduction pathways in mechanosensing in HSC activation in vitro; 2) To determine the role of matrix stiffness in PF activation and to develop a mechanical model of the liver that incorporates HSC and PF activation; 3) To identify the mediators of matrix stiffness in vivo and to determine their role in fibrosis. The proposed studies will provide important new information about the factors involved in myofibroblast transdifferentiation in liver fibrosis, offering the potential for significant advancement in understanding and treating fibrosis, particularly in the identification of new factors regulating early fibrosis.

描述（由申请人提供）：肝纤维化和肝硬化是多种原因导致的慢性肝病的最终结果，在美国每年影响 400,000 人，并导致超过 20,000 人死亡。当多种细胞类型激活成纤维化、表达α-平滑肌肌动蛋白（α-SMA）的肌成纤维细胞时，纤维化发生在细胞水平。在肝脏中，肝星状细胞（HSC）和门静脉成纤维细胞（PF）被认为是两种最重要的活化细胞类型。尽管进行了十年的深入研究，但对介导 HSC 和 PF 激活的因素仍知之甚少。我们研究了 HSC 体外激活过程，并提出了一个初步的两步模型，其中肌成纤维细胞表型是由机械因素和可溶性因素之间的相互作用产生的。在此模型中，当受到细胞外基质 (ECM) 的机械张力时，HSC 表达 α-SMA，然后在通过细胞质信号传导中间体 SmadS 的 TGF-β 信号传导的影响下，将 α-SMA 组织成应力纤维，变得完全激活的肌成纤维细胞。该提案的目的是详细了解机械因素（粘附依赖性机械张力）在体外和体内肝肌成纤维细胞活化中的作用。我们的假设是，在 TGF-β 信号传导背景下，ECM 的机械特性对于纤维化过程中 HSC 和 PF 向肌成纤维细胞的激活至关重要。我们建议通过三个具体目标来解决这一目标和假设：1）确定整合素和下游信号转导途径在体外 HSC 激活的机械传感中的作用； 2) 确定基质刚度在 PF 激活中的作用，并开发结合 HSC 和 PF 激活的肝脏机械模型； 3) 鉴定体内基质硬度的介质并确定它们在纤维化中的作用。拟议的研究将提供有关肝纤维化中肌成纤维细胞转分化所涉及因素的重要新信息，为理解和治疗纤维化提供重大进展，特别是在识别调节早期纤维化的新因素方面。