Role of microRNAs in HSC-mediated fibrogenesis

microRNA 在 HSC 介导的纤维发生中的作用

• 批准号: 9001886
• 负责人: LAURA W SCHRUM
• 金额: $ 20.7万
• 依托单位: CAROLINAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001886
• 关键词: 3' Untranslated Regions; Address; Affect; Alcoholism; Alcohols; Animal Model; Attention; Binding; Biogenesis; Cause of Death; Cessation of life; Chronic; Cicatrix; Cirrhosis; Collagen; Deposition; Development; Down-Regulation; Economic Burden; Effector Cell; Etiology; Event; FDA approved; Fibrosis; Foundations; Functional disorder; Future; Gene Expression; Generic Drugs; Health; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Human; In Vitro; Injury; Lead; Left; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Morbidity - disease rate; Normal tissue morphology; Obesity; Organ; Pathology; Patients; Primary carcinoma of the liver cells; Process; Production; Progressive Disease; Rattus; Regulation; Resolution; Role; Signal Transduction; Staging; Stimulus; Testing; Therapeutic; Transforming Growth Factor beta; Untranslated RNA; Virus; Wound Healing; adeno-associated viral vector; cell growth regulation; chronic alcohol ingestion; chronic liver disease; fibrogenesis; in vivo; innovation; insight; liver transplantation; mRNA Expression; mortality; novel; novel therapeutics; overexpression; protein expression; receptor; response; restoration; therapeutic target; transdifferentiation

DESCRIPTION (provided by applicant): Hepatic fibrosis is a significant cause of morbidity and mortality worldwide. Fibrosis can be characterized as an exacerbated wound-healing response to chronic injury, and if unresolved, may proceed to cirrhosis. A variety of hepatic insults, namely chronic ethanol consumption, can lead to development of fibrosis/cirrhosis. The hepatic stellate cell (HSC) is considered the main effector cell in liver fibrosis as it produces excessive amounts of collagen scar matrix leading to organ dysfunction. Transforming growth factor beta (TGF�) is the most potent profibrogenic molecule stimulating HSC activation and subsequently collagen deposition. Currently, there are no FDA-approved treatments for liver fibrosis/cirrhosis, and liver transplant remains the only cure for cirrhosis. Recent attention has been focused on the regulatory role of microRNAs (miRs) in liver disease pathology, and they show great potential for therapeutic strategies in management of hepatic fibrosis. Specifically, we demonstrated miR19b is significantly decreased in HSCs from fibrotic rat and human liver compared to normal tissue. Mechanistically, overexpression of miR19b inhibits Transforming Growth Factor beta (TGF�) signaling and subsequent collagen production and activation of the HSC via direct binding to the 3'UTR of TGF� Receptor II mRNA. Overall, establishing treatments for fibrosis/cirrhosis will decrease yearly deaths and US economic burden. Therefore, the current application will address the following specific aims: 1) establish cellular mechanisms regulating miR19b biogenesis in the HSC which will lay the foundation for future means of manipulating endogenous expression in vivo, and 2) test miR19b as an effective anti-fibrotic treatment in vivo.

描述（由申请人提供）：肝纤维化是全世界发病和死亡的重要原因。纤维化的特点是对慢性损伤的伤口愈合反应加剧，如果得不到解决，可能会发展为肝硬化。各种肝脏损伤，即慢性乙醇消耗，可导致纤维化/肝硬化的发展。肝星状细胞（HSC）被认为是肝纤维化的主要效应细胞，因为它产生过多的 大量胶原蛋白疤痕基质导致器官功能障碍。转化生长因子 β (TGF�) 是最有效的促纤维化分子，可刺激 HSC 活化和随后的胶原蛋白沉积。目前，尚无 FDA 批准的肝纤维化/肝硬化治疗方法，肝移植仍然是治疗肝硬化的唯一方法。最近的注意力集中在 microRNA (miR) 在肝病病理学中的调节作用，它们在肝纤维化治疗策略方面显示出巨大的潜力。具体来说，我们证明与正常组织相比，纤维化大鼠和人肝脏的 HSC 中 miR19b 显着减少。从机制上讲，miR19b 的过度表达通过直接结合 TGFβ 受体 II mRNA 的 3'UTR 来抑制转化生长因子 β (TGFβ) 信号传导以及随后的胶原蛋白产生和 HSC 激活。总体而言，建立纤维化/肝硬化治疗方法将减少每年的死亡人数和美国的经济负担。因此，当前的应用将解决以下具体目标：1）建立调节HSC中miR19b生物发生的细胞机制，这将为未来操纵体内内源表达的方法奠定基础；2）测试miR19b作为体内有效的抗纤维化治疗。

项目成果

Processing of miR17-92 Cluster in Hepatic Stellate Cells Promotes Hepatic Fibrogenesis During Alcohol-Induced Injury.

• DOI: 10.1111/acer.13116
• 发表时间: 2016-07
• 期刊: Alcoholism, clinical and experimental research
• 作者: Brandon-Warner E;Feilen NA;Culberson CR;Field CO;deLemos AS;Russo MW;Schrum LW
• 通讯作者: Schrum LW

Development of a population pharmacokinetic model of olanzapine for Chinese health volunteers and patients with schizophrenia.

• DOI: 10.1136/bmjopen-2017-020070
• 发表时间: 2018-08-17
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Li A;Ji S;Yue W;Yan H;Dong F;Ruan C;Li W;Lu W;Zhang D;Wang C
• 通讯作者: Wang C

Prospective memory performance in non-psychotic first-degree relatives of patients with schizophrenia: a controlled study.

• DOI: 10.1371/journal.pone.0111562
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhou FC;Hou WM;Wang CY;Ungvari GS;Chiu HF;Correll CU;Shum DH;Man D;Liu DT;Xiang YT
• 通讯作者: Xiang YT

A two-stage association study suggests BRAP as a susceptibility gene for schizophrenia.

• DOI: 10.1371/journal.pone.0086037
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhang F;Liu C;Xu Y;Qi G;Yuan G;Cheng Z;Wang J;Wang G;Wang Z;Zhu W;Zhou Z;Zhao X;Tian L;Jin C;Yuan J;Zhang G;Chen Y;Wang L;Lu T;Yan H;Ruan Y;Yue W;Zhang D
• 通讯作者: Zhang D