Post-Transcriptional Regulation of Lung Fibrosis.

项目摘要/摘要 特发性肺纤维化(IPF)是一种以过度沉积为特征的致死性进行性纤维性疾病。 细胞外基质(ECM)蛋白。持续性的肌成纤维细胞激活被认为是驱动力之一 这会导致IPF中ECM蛋白的过度产生和纤维化。永久化的分子机制 IPF中持续的肌成纤维细胞激活和促纤维化反应尚未完全了解。KH-型 剪接调节蛋白是一种参与转录后调控的mRNA不稳定蛋白。 基因表达。初步数据显示，KSRP在IPF肺中的表达显著降低 成纤维细胞和组织与正常人肺成纤维细胞和组织相比。然而，这个角色 KSRP在肺纤维化中的表达，以及病理性KSRP下调在促纤维化中的功能后果 在IPF中的反应是完全未知的。该提案旨在揭示KSRP在 肺纤维化及其分子机制。初步数据显示KSRP缺陷小鼠 与博莱霉素反应的野生型小鼠相比，KSRP增加了肺纤维化 KSRP的缺乏促进了肌成纤维细胞的分化和ECM蛋白的产生，而KSRP的获得抑制了肌成纤维细胞的分化和ECM蛋白的产生。 这些数据表明，KSRP是纤维化反应的限制因子，并损害KSRP的功能 促进纤维化反应和肺纤维化。此外，KSRP负性调节Migfilin mRNA的稳定性 KSRP缺乏导致Migfilin表达增加。我们的初步数据显示 米非林起着“促肝纤维化开关”的作用，促进促肝纤维化反应。米非林是必需的 肌成纤维细胞的分化和存活。根据初步数据，我们假设KSRP作为一个 肺纤维化的限制性调节，而KSRP功能受损会促进“促纤维化的利基”的形成 Migfilin和Migfilin介导的持续性肌成纤维细胞分化和促纤维化反应 发信号。为了验证这一假设，本文提出了三个具体目标。特定的目标1将决定 KSRP调控肌成纤维细胞分化和存活的机制。特定的AIM 2将决定 KSRP在调控ECM表达和基质组装中的限制性作用。特定的AIM 3将检查 体内细胞特异性KSRP在纤维化形成和功能后果中的作用。这些发现将有助于 了解IPF中持续性肌成纤维细胞激活和促纤维化反应的机制 并为我的长期目标服务，为IPF开发有效的治疗方法。

PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic disease characterized with excessively deposited extracellular matrix (ECM) proteins. Persistent myofibroblast activation is considered as one of driving forces that lead to excessive ECM protein production and fibrosis in IPF. The molecular mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF have not been fully understood. KH-Type Splicing Regulatory Protein (KSRP) is a mRNA destabilizing protein involved in post-transcriptional regulation of gene expression. Preliminary data demonstrate that KSRP expression is significantly decreased in IPF lung fibroblasts and tissues when compared to that in normal human lung fibroblasts and tissues. However, the role of KSRP in lung fibrosis, and the functional consequences of pathologic KSRP downregulation in pro-fibrotic responses in IPF, are completely unknown. This proposal aims to reveal the novel restrictive role of KSRP in lung fibrosis and the molecular mechanisms involved. Preliminary data demonstrate that KSRP deficient mice have increased lung fibrosis when compared to wild-type mice in response to Bleomycin, and that KSRP deficiency promotes, while gain of KSRP inhibits, myofibroblast differentiation and ECM protein production. These data indicate that KSRP functions as a restricting factor of fibrotic reactions, and impaired KSRP function promotes fibrotic reactions and lung fibrosis. Furthermore, KSRP negatively regulates Migfilin mRNA stability and expression and KSRP deficiency results in increased Migfilin expression. Our preliminary data demonstrate that Migfilin functions as a “pro-fibrotic switch”, promoting pro-fibrotic reactions. Migfilin is required for myofibroblast differentiation and survival. Based on preliminary data, we hypothesize that KSRP functions as a restrictive regulator of lung fibrosis, and that impaired KSRP function fosters a “pro-fibrotic niche” fueling persistent myofibroblast differentiation and pro-fibrotic responses mediated by Migfilin and Migfilin mediated signaling. To test the hypothesis, three specific AIMs are proposed. Specific AIM 1 will determine the mechanisms by which KSRP regulates myofibroblast differentiation and survival. Specific AIM 2 will determine the restrictive role of KSRP in controlling ECM expression and matrix assembly. Specific AIM 3 will examine the in vivo cell-specific role of KSRP in fibrogenesis and functional consequences. The findings will help to understand the mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF and serve my long-term goal to develop effective therapy for IPF.