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: 8473261
• 负责人: CRAIG A HENKE
• 金额: $ 15.43万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473261
• 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.

描述（由适用提供）：特发性肺纤维化（IPF）是一种进行性致命的纤维化肺部疾病，没有有效的治疗。哨兵形态病变是I型胶原蛋白含量的成纤维细胞。表面上的证据支持肌纤维细胞在IPF的不断发展中的关键作用，因为这是该细胞在该细胞中增殖和沉积的细胞在该细胞中强烈支持以下观点：IPF成纤维细胞表现出独特的病理表型，而在IPF纤维纤维纤维纤维纤维范围内的差异中仍然存在较大的病理表型，而较大的差距仍然存在差异。用于正常的肺修复。该建议的目的是表征IPF成纤维细胞病理性质的分子过程。开创性研究表明，聚合I型胶原蛋白是成纤维细胞增殖的负调节剂。与此一致，我们发现聚合胶原蛋白抑制了正常的肺成纤维细胞增殖。相比之下，我们发现IPF成纤维细胞逃脱了这种约束。我们对这种现象的机械研究表明，与I型胶原蛋白的连接响应1个整联蛋白信号传导异常。我们发现整联蛋白-ECM相互作用调节PTEN表达和活性。 PTEN是一种磷酸酶，其基线活性始终高。它通过抑制整联蛋白 - 磷酸3-激酶（PI3K）/AKT信号通路来通过负调节的增殖来充当肿瘤抑制器。当正常的肺成纤维细胞在聚合胶原蛋白上培养时，我们发现PTEN活性仍然很高。相反，当在聚合胶原蛋白PTEN活性上培养IPF成纤维细胞时，不适当地将PI3K/AKT信号传导途径不受约束，并消除了主要的物理负反馈信号调节性增殖之一。这使IPF成纤维细胞能够规避聚合胶原蛋白的负调节作用。我们假设这一点：�1整联蛋白型I胶原蛋白相互作用导致PTEN的异常调节。这导致了无限制的PI3K/AKT/S6K1活性，并构成了IPF成纤维细胞在聚合胶原蛋白上的病理增殖。为了检验我们的假设，我们将：目标1。确定PI3K/AKT/S6K1-PTEN信号轴的作用在使IPF成纤维细胞洗脱I型I型胶原蛋白的负增殖效应中。 AIM 2。定义对控制和IPF肺成纤维细胞的PTEN和PIN3K/AKT信号途径调节的分子基础。1个整合蛋白型I胶原蛋白相互作用。目标3。验证体外素pi3k/akt/akt/s6k1-pten信号轴在IPF纤维发生中通过体内方法论中的异常功能的验证。