Mechanisms of myofibroblast survival in fibrosis

(申请人摘要)特发性肺纤维化/常见间质 肺炎(IPF/UIP)是一种致命的实质性肺部疾病，其特征是 肺间质和肺泡间质纤维增生及其临床表现 肌成纤维细胞。肌成纤维细胞的作用机制知之甚少。 IPF/UIP中的积聚或它们未能消除的原因 正常的伤口修复。这个实验室和其他实验室之前的研究已经 研究表明，生存因子，特别是IGF-I，由 IPF/UIP中巨噬细胞和肺泡上皮细胞。在这项提案中，我们 将检验这样一个假设，即包括IGF-I在内的生存因素的存在， 在IPF/UIP保护的患者的实质和空间中 肌成纤维细胞不受凋亡的影响。在这些条件下，肌成纤维细胞 建议在数量上积累，从而可以促进实质 长时间的纤维化。这项提议的主要目标是 三重：(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的凋亡 停药；(Ii)确定IGF-I如何保护肌成纤维细胞 进行细胞凋亡；以及(Iii)研究调控失调的机制 IPF/UIP中肌成纤维细胞凋亡的变化。这些目标将由四个方面来实现 明确的目标。具体目标一将解决增长因素的作用， 力与IGF-I在肌成纤维细胞分化中的作用 成纤维细胞表型与细胞凋亡。这些研究将形成以下基础 用焦点确定促进肌成纤维细胞凋亡的机制 关于半胱氨酸天冬氨酸酶的激活机制(目标二)。的目标是 具体目标三是揭示IGF-I通过哪些机制预防 死亡计划的启动。这些研究的重点将包括 效应器被膜(3、6和7)失活的机制和 抗凋亡蛋白的潜在作用。最后，在具体目标四中，我们 建议将从这项研究中学到的东西应用于 关于解决促进保护免受细胞凋亡的机制的建议 IPF/UIP患者的肺组织。这项工作的结果是可想而知的 为肌成纤维细胞凋亡的机制和机制提供新的见解 这一过程在IPF/UIP中变得失调。

(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.