Targeted delivery of PCBP2 siRNA for treating alcoholic liver fibrosis

描述（由申请人提供）：肝纤维化/肝硬化是一个全球性的健康问题，也是世界上发病率和死亡率的主要原因之一。酒精滥用是西方发达国家肝纤维化/肝硬化最常见的原因之一，占肝硬化病例的50%以上。酒精性肝纤维化是一个涉及多种细胞因子的复杂过程，目前尚无标准的治疗方法。虽然肝纤维化是可逆的，可治疗的，但如果不及时治疗，它将发展到终末期利耶硬化，这是不可逆的，不可治疗的。因此，迫切需要有效的抗肝纤维化药物。我们的策略是逆转在纤维形成结束时形成的过度产生的I型胶原蛋白。这是有效治疗酒精性肝纤维化的最关键的一步，因为无论采用何种治疗，纤维化肝脏中积累的I型胶原都必须逆转。我们提出了siRNA沉默PCBP 2基因表达，随后导致胶原蛋白1（I）mRNA的不稳定，并最终逆转积累的I型胶原蛋白。最近，我们已经证明，酒精上调PCBP 2在肝星状细胞（HSC）的表达。此外，我们已经确定了一种siRNA，可以沉默PCBP 2基因，随后增加HSC中胶原蛋白1（I）mRNA的衰减速率。目前提案中概述的研究专门设计用于通过使用靶向siRNA纳米复合物阻断PCBP 2的表达来治疗实验动物的酒精性肝纤维化。本申请的总体目标有两个：1）开发基于抗生物素蛋白的纳米复合物，以克服PCBP 2 siRNA的两个潜在障碍（稳定性差和缺乏对HSC的靶向能力）; 2）使用各种体外和体内模型评估其治疗有效性。我们的中心假设是，逆转积累的I型胶原在治疗酒精性肝纤维化中至关重要。我们所提出的研究成果有望为开发其他siRNA治疗肝病提供循证基础。

DESCRIPTION (provided by applicant): Liver fibrosis/cirrhosis is a global health problem and one of the leading causes of morbidity and mortality in the world. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in western developed countries, accounting for more than 50% of cirrhosis cases. Alcoholic liver fibrogenesis is a complicated process involving many cytokines, and unfortunately, there is no standard treatment for liver fibrosis till now. Whil liver fibrosis is reversible and treatable, if left untreated, it will develop to the end stage, lier cirrhosis, which is irreversible and untreatable. Therefore, effective antifibrotic medicines are needed urgently. Our strategy is to reverse the over-produced type I collagen which is formed at the end of fibrogenesis. It is the most critical step toward the effective therapy of alcoholic livr fibrosis because the accumulated type I collagen in fibrotic liver has to be reversed no matter what treatment is employed. We proposed siRNA to silence the PCBP2 gene expression, subsequently leading to destabilization of the collagen ¿1(I) mRNA and eventually the reversal of the accumulated type I collagen. Recently, we have proved that alcohol up-regulates the expression of PCBP2 in Hepatic Stellate Cells (HSCs). Moreover, we have identified a siRNA that can silence the PCBP2 gene and subsequently increase the decay rate of collagen ¿1(I) mRNA in HSCs. The research outlined in the current proposal has been designed specifically to treat alcoholic liver fibrosis in experimental animals via blocking the expression of PCBP2 using a targeted siRNA nanocomplex. The overall objectives in the application are two-fold: 1) to develop the avidin-based nanocomplex to overcome the two potential obstacles (poor stability and lack of target-ability to HSCs) of PCBP2 siRNA; 2) to evaluate its therapeutic effectiveness using various in vitro and in vivo models. Our central hypothesis is that the reversal of the accumulated type I collagen is critical in treatment of alcoholic liver fibrosis. Accomplishments o our proposed studies are expected to provide an evidence-based foundation for development of other siRNA therapeutics for liver diseases.