Integrin-collagen signaling and control of fibroblast proliferation

整合素胶原信号传导和成纤维细胞增殖的控制

• 批准号: 8269781
• 负责人: CRAIG A HENKE
• 金额: $ 16.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-04 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269781
• 关键词: Alveolar; Alveolar wall; Apoptosis; Applications Grants; Architecture; Area; Behavior; Bleomycin; Bone Marrow; Cells; Chronic; Collagen; Collagen Type I; Complex; Defect; Deposition; Disease; Extracellular Matrix; Facies; Feedback; Fibroblasts; Fibronectins; Fibrosis; Goals; Growth; Hamman-Rich syndrome; Healed; Health; In Vitro; Inflammation; Inflammatory; Injury; Integrins; Interstitial Lung Diseases; Knockout Mice; Knowledge; Left; Lesion; Ligation; Lipids; Lung; Lung diseases; Membrane; Mesenchymal; 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; base; caveolin 1; effective therapy; fibrogenesis; healing; in vivo; lung development; lung injury; lung repair; mRNA Expression; mTOR Inhibitor; member; protein expression; repaired; response; restraint; therapeutic target; tissue repair; transcription factor

DESCRIPTION (provided by applicant): 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 IPF fibroblasts 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 ¿1 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 as a tumor suppressor by negatively regulating proliferation by repressing the integrin-phosphoinositol 3-kinase (PI3K)/Akt signaling pathway. When normal lung fibroblasts are cultured on polymerized collagen, we have found that 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 and removing one of the major physiological negative feedback signals regulating proliferation. This enables IPF fibroblasts to circumvent the negative regulatory effects of polymerized collagen. We hypothesize that: ¿1 integrin-type I collagen interaction results in aberrant regulation of PTEN. This leads to unrestrained PI3K/Akt/S6K1 activity and underlies the pathologic proliferation of IPF fibroblasts on polymerized collagen. 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 ¿1 integrin-type I collagen interaction. Aim 3. Validation of in vitro studies implicating abnormal function of the ¿1 integrin PI3K/Akt/S6K1-PTEN signaling axis in IPF fibrogenesis by in vivo methodology. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal interstitial lung disease. The sentinel morphological lesion is the fibroblastic focus, which is composed of fibroblasts embedded in a type I collagen rich matrix. Seminal studies have demonstrated that polymerized type I collagen acts as a negative regulator of fibroblast proliferation. We have discovered that IPF fibroblasts have escaped this restraint. Our mechanistic studies of this phenomenon point to aberrant proliferation signaling through the ¿1 integrin, involving the downstream phosphoinositol 3-kinase/Akt - PTEN axis. The objective of this grant application is to characterize the molecular mechanism by which ¿1 integrin-collagen interaction results in abnormal proliferative signaling in IPF fibroblasts. It is our goal to uncover those components of the myofibroblast cellular machinery that result in unrelenting fibrosis in IPF, and in proper tissue healing under normal circumstances. Identifying key regulatory nodes controlling the pathologic behavior of IPF fibroblasts may provide molecular therapeutic targets to limit the progressive fibrosis that characterizes IPF.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种进行性、致命性纤维化肺病，尚无有效治疗方法。前哨形态病变是成纤维细胞病灶，由富含 I 型胶原蛋白的基质中的肌成纤维细胞组成。初步证据支持肌成纤维细胞在 IPF 的持续进展中发挥关键作用，因为肌成纤维细胞在体内增殖和沉积胶原蛋白。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，但在导致进行性纤维化的 IPF 成纤维细胞的病理性质和正常肺修复目标所必需的肌成纤维细胞的生理功能之间仍然存在巨大的认识差距。该提案的目的是描述 IPF 成纤维细胞病理本质的分子过程。 开创性研究表明，聚合 I 型胶原蛋白可作为成纤维细胞的负调节剂。与此一致的是，我们发现正常的肺成纤维细胞增殖受到聚合胶原的抑制，相反，我们发现 IPF 成纤维细胞却逃脱了这种限制。 1 整合素信号传导响应与 I 型胶原的连接，我们发现整合素-ECM 相互作用可调节 PTEN 的表达和活性。当正常肺成纤维细胞在聚合体上培养时，整合素磷酸肌醇 3 激酶 (PI3K)/Akt 信号通路。相比之下，当 IPF 成纤维细胞在聚合胶原上培养时，PTEN 活性不适当地低，从而使 PI3K/Akt 信号通路不受限制，并消除了调节增殖的主要生理负反馈信号之一。 IPF 成纤维细胞规避聚合胶原蛋白的负面调节作用我们追求的是： ¿ 1 整合素 I 型胶原相互作用导致 PTEN 的异常调节，从而导致 PI3K/Akt/S6K1 活性不受限制，并成为 IPF 成纤维细胞在聚合胶原上病理性增殖的基础。 PI3K/Akt/S6K1-PTEN 信号轴使 IPF 成纤维细胞逃避负面增殖效应目的 2. 通过 ¿ 确定对照和 IPF 肺成纤维细胞中 PTEN 和 PI3K/Akt 信号通路调节的分子基础。 1 整合素-I 型胶原相互作用 目标 3. 验证 ¿ 异常功能的体外研究。体内方法研究 IPF 纤维化中的 1 整合素 PI3K/Akt/S6K1-PTEN 信号轴 公共健康相关性：特发性肺纤维化 (IPF) 是一种慢性、致命性间质性肺疾病，前哨形态病变是由成纤维细胞组成。嵌入富含 I 型胶原蛋白基质的成纤维细胞的研究表明，聚合的 I 型胶原蛋白具有作用。作为成纤维细胞增殖的负调节因子，我们发现 IPF 成纤维细胞已经逃脱了这种限制。我们对这种现象的机制研究表明，通过 ¿ 1 整合素，涉及下游磷酸肌醇 3-激酶/Akt - PTEN 轴 该资助申请的目的是表征 ¿ 1 整合素-胶原蛋白相互作用导致 IPF 成纤维细胞异常增殖信号 我们的目标是揭示导致 IPF 持续纤维化的肌成纤维细胞机制的组成部分，并识别正常情况下控制组织正常愈合的关键节点。 IPF 成纤维细胞的病理行为可能提供分子治疗靶点，以限制 IPF 特征的进行性纤维化。