Integrin-ECM regulation of fibroblast proliferation

整合素-ECM 对成纤维细胞增殖的调节

• 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
• 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

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）是一种进行性致命的纤维化肺部疾病，没有有效 治疗。前哨形态病变是成纤维细胞的焦点，由肌纤维细胞组成 I型胶原蛋白含量。 Prima Facie证据支持肌纤维细胞在无情中的关键作用 IPF的进展是这是在肺泡壁中增殖和沉积胶原蛋白的细胞。 尽管研究强烈支持ipffibroplasts表现出不同的病理表型的观念，但 关于IPF成纤维细胞的病理性质之间的差异，知识的差距仍然很大 负责进行性纤维化和肌纤维细胞的生理功能，对正常肺必不可少 维修。该建议的目的是表征病理学基础的分子过程 IPF成纤维细胞的性质。开创性的研究表明，聚合I型胶原蛋白充当 成纤维细胞增殖的负调节剂。与此一致，我们发现正常的肺成纤维细胞 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 逃脱了这种约束。我们对这种现象的机械研究表明01整合素的异常 用I型胶原蛋白的连接响应信号。我们发现整合素ECM的相互作用 调节PTEN表达和活性。 PTEN是一种磷酸酶，其基线活性是组成性的 高的。它通过抑制整合素PI3K/AKT信号通路来负调节增殖来发挥作用。 当在聚合胶原蛋白上培养正常的肺成纤维细胞时，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PTEN活性上培养时，不适当地较低 pi3k/akt信号通路未受限。我们假设在ipffibrosprosss中01 Integin-type I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信号转导轴，使IPF成纤维细胞避免了阴性增殖 聚合I型胶原蛋白的影响。 AIM 2。定义调节PTEN和PTEN的分子基础 在控制和IPF肺成纤维细胞中，PI3K/AKT信号途径由01 Integin-Type I胶原蛋白相互作用。目标3。 体外研究的验证，涉及01整合素PI3K/AKT/S6K1-PTEN信号的异常功能 IPF纤维化中的轴通过体内方法论。 相关性（请参阅说明）： 肌纤维细胞是无情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夸大了增殖。该机制涉及低PTEN 促进PI3K/AKT信号异常激活的活性。这些研究将描绘分子 IPF成纤维细胞中病理较低的PTEN活性的过程并提出了新的疗法。