miR-101 Control of Pulmonary Fibrosis

miR-101 控制肺纤维化

基本信息

批准号：
8847381
负责人：
LIN LIU
金额：
$ 35.76万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847381
关键词：
Advanced Development Affect American Attenuated Bleomycin Cell Proliferation Cell membrane Cells Chronic DNA Binding Deposition Depressed mood Down-Regulation ETS2 gene Extracellular Matrix Fibroblasts Fluorescein-5-isothiocyanate Foundations Gene Transfer Goals Growth Factor Receptors Hamman-Rich syndrome Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Mental Depression MicroRNAs Modeling Molecular Mus Myofibroblast Outcome Pathogenesis Pathway interactions Patients Proliferating Pulmonary Fibrosis Regulation Relative (related person)Signal Pathway Signal Transduction TGFBR1 gene Testing Therapeutic Effect Transcriptional Regulation Transforming Growth Factors Untranslated RNA effective therapy fibroblast-activating factor in vivo interstitial knock-down nuclear factors of activated T-cells public health relevance receptor transcription factor

项目摘要

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.

描述（由申请人提供）：特发性肺纤维化 (IPF) 是一种慢性间质性肺病，每年影响 200,000 名美国人，中位生存期约为 3 年。除了肺移植外，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。细胞外基质过多，导致肺纤维化，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。了解 IPF 中成纤维细胞增殖和激活的分子机制至关重要，PI 的长期目标是阐明 IPF 的发病机制，从而推进有效药物治疗的开发。当前的应用是了解 IPF 中成纤维细胞增殖和激活所涉及的信号通路的 microRNA 调节，尽管人们对典型的 Wnt/¿ -连环蛋白和转化生长因子-¿ (TGF-¿) 信号通路参与 IPF，但人们对 IPF 中的非典型 Wnt/激活 T 细胞核因子 (NFAT) 信号传导知之甚少，MicroRNA（小非编码 RNA）因其重要性而日益受到认可。然而，初步研究表明 miR-101 在 IPF 患者的肺部表达下调，目前尚不清楚哪些 microRNA 以及它们如何调节 IPF 中的信号通路。 Wnt/NFAT 信号传导的激活刺激成纤维细胞增殖，并且 miR-101 抑制 Wnt/NFAT 诱导的成纤维细胞增殖和 TGF-¿ - 通过靶向细胞膜受体刺激成纤维细胞活化该提议的总体假设是，miR-101 的下调通过 Wnt/NFAT 信号传导促进驻留成纤维细胞增殖，并通过 TGF-¿ 刺激成纤维细胞活化，从而导致肺纤维化。目标 I 将确定 TGF-¿ 对 miR-101 的转录调节。目标 II 将描述 miR-101 介导的成纤维细胞增殖和激活抑制的机制，目标 III 将评估 miR-101 对体内肺纤维化的影响。 -101 在 IPF 中的作用，鉴定 miR-101 及其靶点作为成纤维细胞增殖和激活的关键因素，并为开发 miR-101 IPF 疗法奠定了基础。