Role of Fox03a in Regulating the IPF Fibroblast Phenotype

Fox03a 在调节 IPF 成纤维细胞表型中的作用

• 批准号: 7932138
• 负责人: CRAIG A HENKE
• 金额: $ 22.65万
• 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: 2009-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932138
• 关键词: Alveolar; Alveolar wall; Apoptosis; Apoptotic; Architecture; Area; BIM Bcl-2-binding protein; Behavior; Cell Cycle; Cell Proliferation; Cells; Chronic; Collagen; Collagen Type I; Data; Defect; Deposition; Disease; Down-Regulation; Fibroblasts; Fibronectins; Fibrosis; Hamman-Rich syndrome; Inflammation; Injury; Integrins; Interstitial Lung Diseases; Knowledge; Lesion; Lung; Lung diseases; Maintenance; Mediating; Molecular; Myofibroblast; N-terminal; Nature; Normal tissue morphology; PTEN gene; Pathologic; Pathway interactions; Phenotype; Phosphorylation; Physiological; Process; Proliferating; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Public Health; Regulation; Resistance; Role; Seminal; Sentinel; Serine; Signal Pathway; Signal Transduction; Staging; Testing; Threonine; Tissues; Transcription Coactivator; Wound Healing; caspase-3; cyclin-dependent kinase inhibitor 1B; effective therapy; inhibitor/antagonist; repaired; response; therapeutic target

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. We have discovered that polymerized type I collagen suppresses normal fibroblast proliferation via high PTEN activity which inhibits the major PI3K/Akt signaling pathway. In contrast, in IPF fibroblasts, the PI3K/Akt signal is aberrantly activated due to inappropriately low PTEN activity and this permits these cells to elude the proliferation suppressive properties of polymerized collagen. We have generated data indicating that in IPF fibroblasts, the activated PI3K/Akt signal inhibits the function of the FoxO3a transcriptional activator. FoxO3a regulates the cell cycle inhibitor protein p27 and apoptosis inducing protein Bim, two critical proteins involved in the control of cell proliferation and survival, respectively. Our mechanistic studies point to integrin-mediated phosphorylation and/or degradation of FoxO3a as the underlying cause of suppression of FoxO3a function in IPF fibroblasts. We suggest that this pathological defect disrupts the function of the FoxO3a transcriptional activator leading to suppression of p27 and Bim. This may confer IPF fibroblasts with a hyper-proliferative and apoptotic-resistant phenotype. To test our hypothesis we will: Aim 1.Examine the hypothesis that the abnormally activated PI3K/Akt pathway suppresses the function of the FoxO3a transcriptional activator in IPF fibroblasts. Aim 2. Examine the functional role and mechanism of FoxO3a regulation of IPF fibroblast proliferation and survival on polymerized collagen. Aim 3. Examine the molecular mechanism by which the activated integrin/PI3K/Akt signaling pathway suppresses FoxO3a function in IPF fibroblasts. PUBLIC HEALTH RLEVANCE: 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. Polymerized type I collagen suppresses normal fibroblast proliferation by a mechanism involving maintenance of high PTEN activity which inhibits the PI3K/Akt signal pathway. However, in IPF fibroblasts the PI3K/Akt signal is aberrantly activated due to low PTEN activity, permitting these cells to elude the proliferation suppressive properties of polymerized collagen. We have generated data indicating that in IPF fibroblasts, activated Akt inhibits the function of the FoxO3a transcriptional activator. FoxO3a regulates the expression of critical proteins involved in the control of cell proliferation and survival. We suggest that disruption of the function of FoxO3a may confer IPF fibroblasts with a hyper-proliferative and apoptotic-resistant phenotype. Identifying key regulatory nodes controlling the pathologic behavior of IPF fibroblasts may provide molecular therapeutic targets to limit the progressive fibrosis that characterizes IPF. 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（由申请方提供）：特发性肺纤维化（IPF）是一种进行性、致死性纤维化肺病，目前尚无有效治疗方法。前哨形态学病变是成纤维细胞病灶，其由富含I型胶原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持续进展中的关键作用，因为肌成纤维细胞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IPF成纤维细胞表现出独特的病理表型的观点，但对于导致进行性纤维化的IPF成纤维细胞的病理性质与正常肺修复所必需的肌成纤维细胞的生理功能之间的差异，仍存在很大的知识差距。本提案的目的是表征IPF成纤维细胞病理性质的分子过程。我们已经发现聚合的I型胶原通过高PTEN活性抑制正常成纤维细胞增殖，所述高PTEN活性抑制主要的PI 3 K/Akt信号传导途径。相反，在IPF成纤维细胞中，由于不适当的低PTEN活性，PI 3 K/Akt信号被异常激活，这使得这些细胞逃避聚合胶原的增殖抑制特性。我们已经产生的数据表明，在IPF成纤维细胞中，激活的PI 3 K/Akt信号抑制FoxO 3a转录激活因子的功能。FoxO 3a调节细胞周期抑制蛋白p27和凋亡诱导蛋白Bim，这两种蛋白分别参与细胞增殖和存活的控制。我们的机制研究指出整合素介导的FoxO 3a磷酸化和/或降解是IPF成纤维细胞中FoxO 3a功能抑制的根本原因。我们认为，这种病理缺陷破坏了FoxO 3a转录激活因子的功能，导致抑制p27和Bim。这可能赋予IPF成纤维细胞过度增殖和抗肿瘤表型。为了验证我们的假设，我们将：目的1.检查异常激活的PI 3 K/Akt通路抑制IPF成纤维细胞中FoxO 3a转录激活因子的功能的假设。目标2.检查FoxO 3a调节IPF成纤维细胞增殖和在聚合胶原上存活的功能作用和机制。目标3.检查活化的整合素/PI 3 K/Akt信号通路抑制IPF成纤维细胞中FoxO 3a功能的分子机制。公共卫生关系：特发性肺纤维化（IPF）是一种慢性、致死性间质性肺病。前哨形态学病变是成纤维细胞病灶，其由包埋在富含I型胶原的基质中的成纤维细胞组成。聚合的I型胶原蛋白通过涉及维持抑制PI 3 K/Akt信号通路的高PTEN活性的机制抑制正常成纤维细胞增殖。然而，在IPF成纤维细胞中，由于低PTEN活性，PI 3 K/Akt信号被异常激活，使得这些细胞逃避聚合胶原的增殖抑制特性。我们已经生成的数据表明，在IPF成纤维细胞中，激活的Akt抑制FoxO 3a转录激活因子的功能。FoxO 3a调节参与控制细胞增殖和存活的关键蛋白质的表达。我们认为FoxO 3a功能的破坏可能赋予IPF成纤维细胞过度增殖和抗肿瘤的表型。确定控制IPF成纤维细胞病理行为的关键调控节点可能提供分子治疗靶点，以限制IPF特征性的进行性纤维化。确定控制IPF成纤维细胞病理行为的关键调控节点可能提供分子治疗靶点，以限制IPF特征性的进行性纤维化。