Integrin-ECM regulation of fibroblast proliferation

整合素-ECM 对成纤维细胞增殖的调节

基本信息

批准号：
8242755
负责人：
CRAIG A HENKE
金额：
$ 41.37万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242755
关键词：
Alveolar Alveolar wall Apoptosis Architecture Area Bleomycin Cells Chronic Collagen Collagen Type I Complex Defect Deposition Disease Effector Cell Extracellular Matrix Facies Feedback Fibroblasts Fibronectins Fibrosis Growth Hamman-Rich syndrome In Vitro Inflammation Injury Instruction Integrins Interstitial Lung Diseases Knowledge Left Lesion Ligation Lipids Lung Lung diseases Membrane Methodology Molecular Mus Myofibroblast Nature Normal tissue morphology PTEN gene Pathologic Pathway interactions Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Physiological Process Proliferating Protein Biosynthesis Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Pulmonary Fibrosis Regulation Role Seminal Sentinel Signal Pathway Signal Transduction Staging Structure of parenchyma of lung Testing Tissues Tumor Suppressor Proteins Validation Wild Type Mouse Wound Healing base caveolin 1 effective therapy fibrogenesis in vivo laser capture microdissection lung development lung injury mRNA Expression mTOR Inhibitor member protein expression repaired response restraint transcription factor

项目摘要

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal fibrotic lung disease for which there is no effective therapy. The sentinel morphological lesion is the fibroblastic focus, which is composed of myofibroblasts in a type I collagen rich matrix. Prima facie evidence supports the critical role for myofibroblasts in the relentless progression of IPF given that this is the cell that proliferates and deposits collagen in the alveolar wall. Although studies strongly support the notion that IPFfibroblasts display a distinct pathological phenotype, large gaps in knowledge remain regarding differences between the pathological nature of IPF fibroblasts responsible for progressive fibrosis and the physiologic function of myofibroblasts essential for normal lung repair. The objective of this proposal is to characterize the molecular processes underlying the pathological nature of IPF fibroblasts. Seminal studies have demonstrated that polymerized type I collagen acts as a negative regulator of fibroblast proliferation. Consistent with this, we have found that normal lung fibroblast proliferation is inhibited by polymerized collagen. In contrast, we have found that IPF fibroblasts have escaped this restraint. Our mechanistic studies of this phenomenon point to abnormalities in 01 integrin signaling in response to ligation with type I collagen. We have discovered that integrin-ECM interaction regulates PTEN expression and activity. PTEN is a phosphatase whose baseline activity is constitutively high. It functions by negatively regulating proliferation by repressing the integrin- PI3K/Akt signaling pathway. When normal lung fibroblasts are cultured on polymerized collagen, PTEN activity remains high. In contrast, when IPF fibroblasts are cultured on polymerized collagen PTEN activity is inappropriately low leaving the PI3K/Akt signaling pathway unrestrained. We hypothesize that in IPFfibroblasts 01 integrin-type I collagen interaction results in aberrant regulation of PTEN. To test our hypothesis we will: Aim 1. Determine the role of the PI3K/Akt/S6K1-PTEN signaling axis in enabling IPF fibroblasts to elude the negative proliferative effects of polymerized type I collagen. Aim 2. Define the molecular basis for regulation of PTEN and the PI3K/Akt signal pathway in control and IPF lung fibroblasts by 01 integrin-type I collagen interaction. Aim 3. Validation of in vitro studies implicating abnormal function of the 01 integrin PI3K/Akt/S6K1-PTEN signaling axis in IPF fibrogenesis by in vivo methodology. RELEVANCE (See instructions): The myofibroblast is the effector cell of the relentless IPF fibrotic response. We have discovered that IPF fibroblasts have exaggerated proliferation on polymerized collagen. The mechanism involves low PTEN activity that facilitates aberrant activation of the PI3K/Akt signal. These studies will delineate the molecular processes underlying the pathologically low PTEN activity in IPF fibroblasts and suggest new therapies.

特发性肺纤维化（IPF）是一种进行性、致命性的纤维化肺病，目前尚无有效治疗方法。治疗。前哨形态学病变是成纤维细胞灶，由肌成纤维细胞组成。富含 I 型胶原蛋白的基质。初步证据支持肌成纤维细胞在无情的环境中发挥着关键作用鉴于这是在肺泡壁中增殖和沉积胶原蛋白的细胞，IPF 的进展。尽管研究强烈支持 IPF 成纤维细胞表现出独特的病理表型的观点，关于 IPF 成纤维细胞病理性质之间的差异，仍然存在巨大的知识差距负责进行性纤维化和正常肺所必需的肌成纤维细胞的生理功能维修。该提案的目的是表征病理学背后的分子过程 IPF 成纤维细胞的性质。开创性研究表明，聚合 I 型胶原蛋白可作为成纤维细胞增殖的负调节因子。与此相一致的是，我们发现正常肺成纤维细胞聚合胶原蛋白抑制增殖。相比之下，我们发现 IPF 成纤维细胞具有逃脱了这种束缚。我们对这种现象的机制研究表明 01 整合素存在异常响应与 I 型胶原连接的信号传导。我们发现整合素-ECM 相互作用调节 PTEN 表达和活性。 PTEN 是一种磷酸酶，其基线活性是组成型的高的。它通过抑制整合素-PI3K/Akt 信号通路来负向调节增殖。当正常肺成纤维细胞在聚合胶原蛋白上培养时，PTEN 活性仍然很高。相比之下，当 IPF 成纤维细胞在聚合胶原蛋白上培养时，PTEN 活性过低，导致 PI3K/Akt 信号通路不受限制。我们假设 IPF 成纤维细胞 01 整合素 I 型胶原蛋白相互作用导致 PTEN 的异常调节。为了检验我们的假设，我们将：目标 1. 确定角色 PI3K/Akt/S6K1-PTEN 信号轴的作用使 IPF 成纤维细胞能够逃避负增殖聚合 I 型胶原蛋白的作用。目标 2. 定义 PTEN 调节的分子基础和对照和 IPF 肺成纤维细胞中 PI3K/Akt 信号通路通过 01 整合素与 I 型胶原相互作用。目标3。验证 01 整合素 PI3K/Akt/S6K1-PTEN 信号传导异常功能的体外研究通过体内方法研究 IPF 纤维形成中的轴。相关性（参见说明）：肌成纤维细胞是持续 IPF 纤维化反应的效应细胞。我们发现IPF 成纤维细胞在聚合胶原蛋白上过度增殖。其机制涉及低PTEN 促进 PI3K/Akt 信号异常激活的活性。这些研究将描述分子 IPF 成纤维细胞中病理性低 PTEN 活性的过程并提出新的治疗方法。