miR-101 Control of Pulmonary Fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是一种慢性间质性纤维化肺疾病，每年影响20万美国人，中位生存期约为3年。除了肺移植，没有有效的治疗方法。IPF的病理特征是形成由大量活化和增殖的成纤维细胞（肌成纤维细胞）组成的成纤维细胞灶。这些细胞沉积过多的细胞外基质，导致肺纤维化。居住成纤维细胞的增殖和活化被认为是IPF发病机制的主要因素之一。然而，导致成纤维细胞扩张和激活的信号通路及其调节因子尚不完全清楚。因此，迫切需要了解成纤维细胞增殖和IPF活化的分子机制。PI的长期目标是阐明IPF的发病机制，从而促进有效药物治疗的发展。当前应用的目的是了解microRNA在IPF中参与成纤维细胞增殖和激活的信号通路的调控。虽然已知典型的Wnt/ -catenin和转化生长因子- (TGF-)信号通路参与IPF，但对于非典型的Wnt/活化t细胞核因子（NFAT）信号通路在IPF中的作用知之甚少。MicroRNAs是一种小的非编码rna，在调节信号通路方面的重要性日益得到认可。然而，哪些microrna以及它们如何调节IPF的信号通路仍不清楚。初步研究表明，miR-101在IPF患者的肺中下调，激活Wnt/NFAT信号刺激成纤维细胞增殖，miR-101通过靶向Wnt/NFAT诱导的成纤维细胞增殖和TGF-¿-刺激成纤维细胞的细胞膜受体抑制其活化。本研究的总体假设是miR-101下调通过Wnt/NFAT信号通路促进成纤维细胞增殖，通过TGF-¿信号通路刺激成纤维细胞活化，从而促进肺纤维化。目的研究TGF-¿信号对miR-101的转录调控作用。Aim II将描述mir -101介导的成纤维细胞增殖和活化抑制的机制。Aim III将在体内评估miR-101对肺纤维化的影响。预期结果是建立miR-101在IPF中的下调机制，确定miR-101及其靶点是成纤维细胞增殖和活化的关键因素，并为开发miR-101治疗IPF奠定基础。

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF), a chronic interstitial fibrotic lung disease, affects 200,000 Americans per year with a median survival of approximately 3 years. There is no effective therapy except lung transplantation. The pathological hallmark of IPF is the formation of fibroblastic foci consisting of a large number of activated and proliferated fibroblasts (myofibroblasts). These cells deposit excessive extracellular matrix, resulting in pulmonary fibrosis. Residential fibroblast proliferation and activation is thought to be one of the major contributors to the pathogenesis of IPF. However, signaling pathways and their regulators leading to fibroblast expansion and activation are not completely understood. Thus, there is a critical need to understand molecular mechanisms of fibroblast proliferation and activation in IPF. The PI's long-term goal is to elucidate the pathogenesis of IPF and thus advance development of effective pharmacological therapy. The objective of the current application is to understand microRNA regulation of the signaling pathways involved in fibroblast proliferation and activation in IPF. Although it is appreciated tha canonical Wnt/¿-catenin and transforming growth factor-¿ (TGF-¿) signaling pathways are involved in IPF, little is known regarding the non-canonical Wnt/Nuclear factor of activated T-cells (NFAT) signaling in IPF. MicroRNAs, small non-coding RNAs, are increasingly recognized for their importance in regulating signaling pathways. However, which microRNAs and how they regulate the signaling pathways in IPF are still unclear. Preliminary studies have demonstrated that miR-101 is down-regulated in the lungs of IPF patients, that the activation of Wnt/NFAT signaling stimulates fibroblast proliferation, and that miR-101 inhibits Wnt/NFAT-induced fibroblast proliferation and TGF-¿- stimulated fibroblast activation by targeting their cell membrane receptors. The overall hypothesis of this proposal is that the down-regulation of miR-101 contributes to pulmonary fibrosis by promoting residential fibroblast proliferation through Wnt/NFAT signaling, and stimulating fibroblast activation through TGF-¿ signaling. Aim I will determine the transcriptional regulation of miR-101 by TGF-¿ signaling. Aim II will delineate the mechanisms of miR-101-mediated inhibition of fibroblast proliferation and activation. Aim III will evaluate the effects of miR-101 on pulmonary fibrosis in vivo. Expected outcomes are establishment of mechanisms for the down-regulation of miR-101 in IPF, identification of miR-101 and its targets as critical factors for fibroblast proliferation and activation, and a foundatin for developing miR-101 therapy for IPF.