MicroRNA regulation of CTGF in hepatic stellate cells

MicroRNA对肝星状细胞CTGF的调控

基本信息

批准号：
8275273
负责人：
DAVID R BRIGSTOCK
金额：
$ 32.58万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-05 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8275273
关键词：
3&apos Untranslated Regions Accounting Affect Alcohols Autoimmune Process Automobile Driving Binding Biogenesis Biology Cause of Death Cell Cycle Progression Cell Proliferation Cells Cellular biology Cessation of life Chronic Cicatrix Collagen Deposition Development Disease E-Box Elements Elements Epithelial Ethanol Exposure to FDA approved Fibrillar Collagen Fibrosis Functional RNA Gene Targeting Genes Genetic Genetic Transcription Goals Health Heart Hepatic Stellate Cell Hepatocyte Human Immigration Individual Injury Introns Kidney Knowledge Lead Light Liposomes Liver Liver Cirrhosis Liver Fibrosis Liver diseases Lung Malignant neoplasm of liver Medical Mesenchymal Metabolism MicroRNAs Mus Organ Outcome Study Pancreas Pathology Pathway interactions Pattern Play Post-Transcriptional Regulation Process Production Public Health RNA Regulation Research Role Signal Transduction Skin Smooth Muscle Actin Staining Method Testing Therapeutic Therapeutic Intervention Tissues Toxin Transcript Transforming Growth Factors United States National Institutes of Health alcohol response base cell type clay connective tissue growth factor effective therapy fibrogenesis improved in vivo in vivo Model liver function mRNA Expression nanoscale nanosized novel novel therapeutics promoter response stemness

项目摘要

DESCRIPTION (provided by applicant): During chronic liver injury, hepatic stellate cells (HSC) produce and deposit excessive quantities of fibrillar collagens leading to scar formation and compromised liver function. This fibrotic process is driven by connective tissue growth factor (CTGF). Our broad long-term objective is to inhibit the production or action or CTGF so that effective anti-fibrotic strategies can be developed for use in humans. The overall objective of this application is to determine the function of microRNA-199a (miR-199a) or mircoRNA-214 (miR-214) in regulating CTGF production in light of our identification of miR-199a/214 as hitherto unrecognized miRs in HSC which function as negative regulators of CTGF mRNA expression. Thus miR-199a/214 are expressed at high levels in quiescent HSC in normal liver thereby inhibiting CTGF production whereas their expression is suppressed during HSC activation after injury leading to enhanced CTGF expression. MiR-199a/214 are exported from HSC via nano-size exosomes, a novel finding that is important since it allows for miR delivery to neighboring cells and regulation of target genes therein. Our central hypothesis is that expression or action of miR-199a/214 in HSC are critical determinants of CTGF mRNA expression. The Aims to test our hypothesis are: [1] Establish mechanisms regulating miR-199a/214 production in HSC [2] Establish the role of miR-199a/214 in HSC activation and fibrosis [3] Establish the role of exosomal miR-199a/214 in intercellular signaling The expected outcome of these studies will be a more complete understanding of the manner in which CTGF production is regulated during HSC activation. The rationale that underlies the proposed research is that once the roles of miR-199a/214 in CTGF regulation are better understood, they may be exploitable as novel anti- fibrotics. Development of new therapies is critical because fibrotic pathology represents one of the largest groups of disorders for which there is no effective therapy. The medical and financial burdens of liver fibrosis are huge: liver cirrhosis is the ninth leading cause of death in the West, affects millions of individuals world- wide, and is a harbinger of hepatic cancer. The proposed studies are responsive to the 2004 trans-NIH "Action Plan for Liver Disease Research and will have a positive impact on improving public health by providing new leads in our understanding of CTGF biology, which is central to the process of liver fibrosis and the development of novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Fibrosis of internal organs is a significant contributing factor in about 45% of the deaths in the USA yet there are currently no FDA-approved anti-fibrotic therapeutics. Chronic fibrosis most commonly affects the liver, lung, kidney, heart, pancreas and skin and is the result of diverse causes such as autoimmune, genetic, idiopathic, or toxins (e.g. alcohol in hepatic fibrosis). These studies will determine the role of connective tissue growth factor (CTGF) in controlling the pro-fibrogenic functions of hepatic stellate cells, which are the principal fibrogenic cell type in the liver. This proposal focuses on identifying the mechanisms by which CTGF production is regulated by small naturally occurring RNA molecules called microRNA. The relevance of these studies is that they will identify key steps in the pathways that lead to hepatic fibrosis and will define points of therapeutic intervention that exploit the central role played by connective tissue growth factor (CTGF) in driving fibrotic pathology.

描述（由申请人提供）：在慢性肝损伤期间，肝星状细胞（HSC）产生并沉积过量的原纤维胶原蛋白，导致疤痕形成和肝功能损害。这种纤维化过程是由结缔组织生长因子（CTGF）驱动的。我们广泛的长期目标是抑制生产，行动或CTGF，以便可以开发出有效的抗纤维化策略供人类使用。该应用的总体目的是确定microRNA-199a（miR-199a）或mircorna-214（miR-214）在调节CTGF产生中的功能，鉴于我们鉴定了MiR-199a/214的鉴定，迄今为止，HSC中未识别的miRs在HSC中未识别的miRS在HSC中未识别，这是CTGF mRNA表达的负调节剂。因此，miR-199a/214在正常肝脏中静态HSC的高水平表达，从而抑制CTGF的产生，而在损伤后HSC激活期间，它们的表达受到抑制，导致CTGF表达增强。 miR-199a/214通过纳米尺寸外泌体从HSC出口，这是一个新颖的发现，这很重要，因为它允许MiR递送到相邻细胞并调节其中的靶基因。我们的中心假设是miR-199a/214在HSC中的表达或作用是CTGF mRNA表达的关键决定因素。 The Aims to test our hypothesis are: [1] Establish mechanisms regulating miR-199a/214 production in HSC [2] Establish the role of miR-199a/214 in HSC activation and fibrosis [3] Establish the role of exosomal miR-199a/214 in intercellular signaling The expected outcome of these studies will be a more complete understanding of the manner in which CTGF production is regulated during HSC activation.提出的研究基础的基本原理是，一旦更好地理解了MiR-199a/214在CTGF调节中的作用，它们就可以被视为新型的抗血纤维制剂。新疗法的发展至关重要，因为纤维化病理是没有有效疗法的最大疾病群体之一。肝纤维化的医疗和财务负担很大：肝硬化是西方第九主要死亡原因影响着数百万个世界，是一个肝癌的预兆。拟议的研究对2004年的NIH“肝病研究行动计划”有反应，并通过在我们对CTGF生物学的理解中提供新的潜在客户，对改善公共卫生产生积极影响，这对于肝纤维化过程和新型治疗策略的发展至关重要。公共卫生相关性：内部器官的纤维化是美国约45％死亡的重要因素，但目前尚无FDA批准的抗纤维化治疗剂。慢性纤维化最常影响肝脏，肺，肾脏，心脏，胰腺和皮肤，是自身免疫性，遗传，特发性或毒素等多种原因的结果（例如，肝纤维化中的酒精）。这些研究将确定结缔组织生长因子（CTGF）在控制肝星状细胞的促纤维化功能方面的作用，肝脏星状细胞是肝脏中的主要纤维基细胞类型。该提案着重于确定机制哪种CTGF产生由称为microRNA的小天然RNA分子调节。这些研究的相关性是，它们将确定导致肝纤维化的途径中的关键步骤，并定义治疗干预点，从而利用结缔组织生长因子（CTGF）在驱动纤维化病理学中所起的核心作用。