Role of microRNAs in HSC-mediated fibrogenesis

描述(由申请者提供)：肝纤维化是全球发病率和死亡率的重要原因。纤维化可以被描述为对慢性损伤的加剧的伤口愈合反应，如果不能解决，可能会发展为肝硬变。各种肝脏损伤，即长期饮酒，可导致纤维化/肝硬化的发展。肝星状细胞(HSC)是肝纤维化的主要效应细胞，因其产生过量的 大量的胶原疤痕基质导致器官功能障碍。转化生长因子-β(TGFR-�)是最强的促纤维化分子，可刺激肝星状细胞活化及随后的胶原沉积。目前，还没有FDA批准的治疗肝纤维化/肝硬变的方法，肝移植仍然是治疗肝硬变的唯一方法。近年来，microRNAs(MiRs)在肝病病理中的调节作用受到关注，它们在肝纤维化的治疗策略中显示出巨大的潜力。具体地说，我们证明了与正常组织相比，纤维化大鼠和人肝HSCs中miR19b显著减少。从机制上讲，miR19b的过表达通过直接与转化生长因子受体II�的3‘端非编码区结合，抑制转化生长因子β信号转导和随后的胶原合成以及肝星状细胞的激活。总体而言，建立对纤维化/肝硬变的治疗将减少每年的死亡人数和美国的经济负担。因此，目前的应用将解决以下具体目标：1)在HSC中建立调节miR19b生物生成的细胞机制，这将为未来体内调控内源性表达的手段奠定基础；2)测试miR19b作为一种有效的体内抗纤维化治疗方法。

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.