Integrin-ECM regulation of fibroblast proliferation

特发性肺纤维化(IPF)是一种进行性、致死性纤维性肺部疾病，目前尚无有效的治疗方法 心理治疗。前哨形态病变为成纤维细胞灶，由成纤维细胞组成。 I型胶原富含基质。初步证据支持肌成纤维细胞在无情的 IPF的进展，因为这是细胞增殖和沉积胶原在肺泡壁。 尽管研究强烈支持IPF成纤维细胞表现出不同的病理表型的观点， 关于IPF成纤维细胞的病理性质之间的差异，人们的认识仍然存在很大差距 与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有关 修理。这项建议的目的是描述在病理基础上的分子过程。 IPF成纤维细胞的性质。开创性研究表明，聚合的I型胶原作为一种 成纤维细胞增殖的负调控因子。与此一致，我们发现正常的肺成纤维细胞 聚合的胶原蛋白可抑制细胞增殖。相反，我们发现IPF成纤维细胞有 逃脱了这种束缚。我们对这一现象的机制研究指出了01整合素的异常 与I型胶原结扎反应的信号转导。我们发现整合素与细胞外基质的相互作用 调节PTEN的表达和活性。PTEN是一种磷酸酶，其基础活性是结构性的 很高。它通过抑制整合素-PI3K/Akt信号通路负向调控细胞增殖。 当正常肺成纤维细胞在聚合胶原上培养时，PTEN活性保持较高水平。相比之下， 当IPF成纤维细胞在聚合胶原上培养时，PTEN活性低得不适当，从而使 PI3K/Akt信号通路不受抑制。我们假设在IPF成纤维细胞01中整合素I型胶原 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信号轴在IPF成纤维细胞逃避负增殖中的作用 聚合的I型胶原的影响。目的2.明确PTEN调控的分子基础 PI3K/Akt信号通路在对照和IPF肺成纤维细胞中通过01整合素-I型胶原相互作用。目标3. 01整合素PI3K/Akt/S6K1-PTEN信号转导功能异常的体外研究验证 AXIS在IPF纤维化形成中的体内方法学研究 相关性(请参阅说明)： 肌成纤维细胞是持续的IPF纤维化反应的效应细胞。我们发现IPF 成纤维细胞在聚合的胶原蛋白上过度增殖。其机制与低PTEN有关 促进PI3K/Akt信号异常激活的活性。这些研究将描绘出 特发性肺间质纤维化成纤维细胞PTEN活性低的致病机制并提出新的治疗方法。

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.