Integrin-ECM regulation of fibroblast proliferation

特发性肺纤维化（IPF）是一种进行性、致死性纤维化肺病，目前尚无有效的治疗方法。 疗法前哨形态学病变是成纤维细胞病灶，其由肌成纤维细胞组成， I型胶原蛋白丰富的基质。初步证据支持肌成纤维细胞在无情的 IPF的进展，因为这是增殖并在肺泡壁中沉积胶原蛋白的细胞。 尽管研究强烈支持IPF成纤维细胞显示出独特的病理表型的观点， 关于IPF成纤维细胞的病理性质之间的差异， 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 修复.这项建议的目的是表征病理性的潜在的分子过程， IPF成纤维细胞的性质。精液研究表明，聚合的I型胶原蛋白作为一种 成纤维细胞增殖的负调节因子。与此一致，我们发现正常的肺成纤维细胞 增殖被聚合的胶原蛋白抑制。相比之下，我们发现IPF成纤维细胞 摆脱了这种束缚。我们对这一现象的机制研究指出，01整合素 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的表达和活性。PTEN是一种磷酸酶，其基线活性是组成型的。 高它通过抑制整合素-PI 3 K/Akt信号通路负性调节增殖发挥作用。 当正常的肺成纤维细胞在聚合的胶原上培养时，PTEN活性仍然很高。与此相反， 当IPF成纤维细胞在聚合的胶原蛋白上培养时，PTEN活性不适当地低， PI 3 K/Akt信号通路不受限制。我们假设在IPF成纤维细胞中，整合素I型胶原 相互作用导致PTEN的异常调节。为了验证我们的假设，我们将：目标1。确定角色 PI 3 K/Akt/S6 K1-PTEN信号转导轴使IPF成纤维细胞逃避负性增殖抑制， 聚合的I型胶原蛋白的作用。目标2.定义调节PTEN的分子基础， 通过01整合素-I型胶原相互作用在对照和IPF肺成纤维细胞中的PI 3 K/Akt信号通路。目标3。 涉及01整联蛋白PI 3 K/Akt/S6 K1-PTEN信号传导的异常功能的体外研究的验证 轴在IPF纤维化中的作用。 相关性（参见说明）： 肌成纤维细胞是持续的特发性肺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上过度增殖。该机制涉及低PTEN 促进PI 3 K/Akt信号异常激活的活性。这些研究将描绘出 这是IPF成纤维细胞中病理性低PTEN活性的基础过程，并提出了新的治疗方法。

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.