Mechanisms of myofibroblast survival in fibrosis

纤维化过程中肌成纤维细胞的存活机制

• 批准号: 6616355
• 负责人: David W. Riches
• 金额: $ 28.87万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616355
• 关键词: apoptosis; cell differentiation; cellular pathology; cysteine endopeptidases; enzyme activity; fibroblasts; human subject; idiopathic pulmonary fibrosis; insulinlike growth factor; muscle cells; patient oriented research; protease inhibitor; pulmonary fibrosis /granuloma

(Applicant's Abstract) Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) is a fatal parenchymal lung disease characterized by interstitial and alveolar fibroproliferation and the appearance of myofibroblasts. Little is known about the mechanisms of myofibroblast accumulation in IPF/UIP or why they fail to be eliminated as occurs during normal wound repair. Previous studies from this and other laboratories have shown that survival factors, especially IGF-I, are abundantly expressed by macrophages and alveolar epithelial cells in IPF/UIP. In this proposal, we will test the hypothesis that the presence of survival factors, including IGF-I, in the parenchyma and airspaces of patients with IPF/UIP protect myofibroblasts from apoptosis. Under these conditions, myofibroblasts are proposed to accumulate in numbers and can thus contribute to parenchymal fibrosis for extended periods of time. The major goals of this proposal are three-fold: (i) to investigate the conditions and mechanisms that mediate myofibroblast apoptosis under conditions of growth factor and stretch withdrawal; (ii) to determine how IGF-I serves to protect myofibroblasts from undergoing apoptosis; and (iii) to investigate the mechanism of dysregulation of myofibroblast apoptosis in IPF/UIP. These goals will be addressed by four specific aims. Specific aim one will address the role of growth factors, physical forces and IGF-I in myofibroblast differentiation, reversion to a fibroblast phenotype and apoptosis. These studies will form a basis for determining the mechanisms that promote myofibroblast apoptosis with a focus on the mechanisms of caspase activation (specific aim two). The objective of specific aim three is to uncover the mechanisms through which IGF-I prevents the initiation of the death program. The focus of these studies will include the mechanism of inactivation of the effector capsases (3, 6 and 7) and the potential role of anti-apoptotic proteins. Lastly, in specific aim four, we propose to apply what has been learned from this studies conducted in this proposal to address the mechanisms that promote protection from apoptosis in the lungs of patients with IPF/UIP. The findings from this work are expected to provide new insights into the mechanism of myofibroblast apoptosis and how this process becomes dysregulated in IPF/UIP.

（申请人摘要）特发性肺纤维化/常见间质性 肺炎（IPF/UIP）是一种致死性实质性肺病，其特征为 间质和肺泡纤维增生， 肌成纤维细胞肌成纤维细胞的作用机制尚不清楚， IPF/UIP中的蓄积，或者为什么它们在 正常的伤口修复该实验室和其他实验室的先前研究 显示存活因子，特别是IGF-I，在细胞中大量表达， 巨噬细胞和肺泡上皮细胞。在本提案中，我们 将检验生存因子，包括IGF-I， 在IPF/UIP患者的实质和气隙中保护 肌成纤维细胞凋亡。在这些条件下，肌成纤维细胞 建议在数量上积累，因此可以有助于实质 纤维化持续时间长。这项建议的主要目标是 三方面：（一）调查调解的条件和机制 生长因子和牵张条件下肌成纤维细胞凋亡 退出;（ii）确定IGF-I如何保护肌成纤维细胞免受 进行细胞凋亡;和（iii）研究失调的机制 IPF/UIP中肌成纤维细胞凋亡。这些目标将通过四个方面来实现。 具体目标。具体目标之一是解决生长因子的作用， 物理力和IGF-I在肌成纤维细胞分化中的作用， 成纤维细胞表型和凋亡。这些研究将为 确定促进肌成纤维细胞凋亡的机制， 半胱天冬酶激活机制（具体目标二）。的目标 第三个具体目标是揭示IGF-I预防糖尿病的机制， 死亡计划的启动这些研究的重点将包括 效应物衣壳酶（3、6和7）的失活机制以及 抗凋亡蛋白的潜在作用。最后，在具体目标四中，我们 我建议把从这项研究中学到的东西应用到这个项目中。 建议解决机制，促进保护细胞凋亡， IPF/UIP患者的肺部。这项工作的结果预计 为肌成纤维细胞凋亡的机制以及 该过程在IPF/UIP中变得失调。