Targeted delivery of PCBP2 siRNA for treating alcoholic liver fibrosis

PCBP2 siRNA 的靶向递送治疗酒精性肝纤维化

• 批准号: 8910579
• 负责人: Kun Cheng
• 金额: $ 32.59万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910579
• 关键词: Accounting; Affect; Affinity; Alcohol abuse; Alcohols; Animals; Avidin; Binding; Biodistribution; Biotin; CCL4 gene; Carbon Tetrachloride; Charge; Cirrhosis; Collagen; Collagen Type I; Developed Countries; Development; Dose; Encapsulated; Extracellular Matrix; Fibrosis; Foundations; Gene Expression; Genes; Goals; Half-Life; Hepatic Fibrogenesis; Hepatic Stellate Cell; In Vitro; Label; Left; Ligands; Ligation; Liver; Liver Fibrosis; Liver diseases; Medicine; Messenger RNA; Methods; Modeling; Modification; Molecular Weight; Morbidity - disease rate; Nitrosamines; Plasma; Polyethylene Glycols; Process; Production; Protamines; RNA-Binding Proteins; Rattus; Relative (related person); Research; Serum; Small Interfering RNA; Staging; Stimulus; Structure; Testing; Therapeutic; Toxicology; Vertebral column; base; bile duct; cytokine; design; effective therapy; evidence base; expectation; experience; fibrogenesis; global health; improved; in vivo; in vivo Model; innovation; intrahepatic; mortality; problem drinker; receptor mediated endocytosis; small hairpin RNA; standard care; targeted delivery; therapeutic effectiveness; uptake

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.

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。在西方发达国家，酒精滥用是导致肝纤维化/肝硬化的最常见原因之一，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，遗憾的是，目前尚无针对肝纤维化的标准治疗方法。虽然肝纤维化是可逆和可治疗的，但如果不加以治疗，它将发展到终末期，即肝硬化，这是不可逆转和不可治疗的。因此，迫切需要有效的抗纤维化药物。我们的策略是逆转过度生产的I型胶原蛋白，它是在纤维形成的最后形成的。这是酒精性肝纤维化有效治疗的最关键一步，因为无论采用何种治疗方法，纤维化肝脏中积累的I型胶原都必须逆转。我们提出siRNA沉默PCBP2基因的表达，随后导致胶原1(I) mRNA的不稳定，最终逆转积累的I型胶原。最近，我们证实了酒精上调肝星状细胞（HSCs）中PCBP2的表达。此外，我们已经发现了一种siRNA，它可以沉默PCBP2基因，随后增加hsc中胶原- 1(I) mRNA的衰变速率。当前提案中概述的研究是专门设计的，通过使用靶向siRNA纳米复合物阻断PCBP2的表达来治疗实验动物的酒精性肝纤维化。该应用的总体目标有两个方面：1)开发基于亲和素的纳米复合物，以克服PCBP2 siRNA的两个潜在障碍（稳定性差和缺乏对造血干细胞的靶向性）；2)利用各种体外和体内模型评价其治疗效果。我们的中心假设是，逆转积累的I型胶原蛋白在治疗酒精性肝纤维化中是至关重要的。我们提出的研究成果有望为开发其他siRNA肝脏疾病疗法提供循证基础。