The Role of ZFP36 in Control of IPF

 描述（由申请方提供）：特发性肺纤维化（IPF）是一种致死性纤维化肺病。迄今为止，尚无改变IPF死亡率或疾病进展的有效疗法。ZFP 36是一种mRNA去稳定蛋白。ZFP 36表达在IPF中显著降低。ZFP 36在肺纤维化中的作用以及病理性ZFP 36下调在纤维化反应中的功能后果是完全未知的。我们的初步数据表明，ZFP 36通过转录后调节机制负调控多种促纤维化介质的表达。降低的ZFP 36表达导致控制IPF肺成纤维细胞中促纤维化反应的反馈环缺陷/失败。重要的是，ZFP 36缺陷型小鼠与野生型小鼠相比，对博来霉素的反应增加了肺纤维化。我们假设ZFP 36通过转录后调节机制作为肺纤维化和促纤维化反应的负调节剂发挥作用。我们进一步假设，由于促纤维化介质mRNA的长期稳定性，IPF中ZFP 36的减少导致促纤维化介质的无节制表达。为了验证我们的假设，提出了三个具体目标。目的1旨在确定ZFP 36在控制促纤维化介质表达中的作用，并确定所涉及的转录后机制。目的2：研究ZFP 36基因缺陷对肺纤维化的影响，探讨ZFP 36基因调控肺纤维化的机制。目的3试图确定病理性ZFP 36下调的分子机制及其在IPF肺成纤维细胞中的后果。这些发现将定义ZFP 36作为肺纤维化负调节因子的新作用，并为ZFP 36缺乏促进促纤维化反应和肺纤维化的分子机制提供新的见解。这项工作支持我们的长期目标，即利用新知识开发新的治疗方法，以抑制IPF的持续性纤维化反应。

 DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease. There is no effective therapy that alters mortality or disease progression in IPF so far. ZFP36 is an mRNA-destabilizing protein. ZFP36 expression is significantly decreased in IPF. The role of ZFP36 in lung fibrosis, and the functional consequence of pathologic ZFP36 downregulation in fibrotic reactions, are completely unknown. Our preliminary data indicate that ZFP36 negatively regulates the expression of multiple pro-fibrotic mediators through a post-transcriptional regulation mechanism. Decreased ZFP36 expression results in a defective/failed feedback loop to control the pro-fibrotic reactions in IPF lung fibroblasts. Importantly, preliminay data demonstrate that ZFP36-deficient mice have increased lung fibrosis when compared to wild-type mice in response to bleomycin. We hypothesize that ZFP36 functions as a negative regulator of lung fibrosis and pro-fibrotic reactions through a post-transcriptional regulation mechanism. We further hypothesize that ZFP36 reduction in IPF results in unbridled expression of pro-fibrotic mediators due to prolonged stability of pro-fibrotic mediator mRNAs. To test our hypothesis, three specific aims are proposed. Aim 1 seeks to define the role of ZFP36 in control of the expression of pro-fibrotic mediators and to determine the post-transcriptional mechanism involved. Aim 2 will determine the functional consequence of ZFP36 deficiency in the development of lung fibrosis in vivo, and explore the mechanisms by which ZFP36 controls lung fibrosis in vivo. Aim 3 seeks to determine the molecular mechanism of pathologic ZFP36 downregulation and its consequences in IPF lung fibroblasts. The findings will define the novel role of ZFP36 as a negative regulator of lung fibrosis, and provide new insights about the molecular mechanism by which ZFP36 deficiency promotes pro-fibrotic responses and lung fibrosis. This work supports our long-term goal to utilize new knowledge to develop novel therapeutic approaches to inhibit the persistent fibrotic reactions in IPF.