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Combination therapy using siRNA nanocompelex and PD-L1 inhibitor for alcoholic liver fibrosis

siRNA纳米复合物与PD-L1抑制剂联合治疗酒精性肝纤维化

基本信息

批准号：
9980233
负责人：
Kun Cheng
金额：
$ 34.89万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
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：
2012-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980233
关键词：
Accounting Adult Affect Alcohol abuse Alcohols Antibodies Apoptosis B-Lymphocytes Binding Biodistribution Biotin Blood Circulation CD8-Positive T-Lymphocytes Carbon Tetrachloride Cells Chemicals Chronic Cirrhosis Clinical Research Collagen Collagen Type I Combined Modality Therapy Critical Pathways Developed Countries Dose Ethanol Event Extracellular Matrix Generations Genes Glycine Goals Half-Life Hepatic Fibrogenesis Hepatic Stellate Cell Human IGF2R gene IL2RA gene Immune Immune response Immunosuppression In Vitro Jurkat Cells Left Length Libraries Ligands Ligation Liver Liver Cirrhosis Liver Fibrosis Mediating Medicine Messenger RNA Modeling Modification Molecular Weight Morbidity - disease rate PD-1 blockade PD-1/PD-L1 PDL1 inhibitors PDL1 pathway Pathway interactions Peptide Nucleic Acids Peptides Polyethylene Glycols Process RNA-Binding Proteins Rattus Regulatory T-Lymphocyte Role Signal Pathway Small Interfering RNA Specificity Surface System T cell response T-Lymphocyte Testing Time United States Vertebral column anti-PD-L1 anti-PD-L1 antibodies base bile duct cytokine design effective therapy experimental study feeding fibrogenesis global health gut microbiota immune clearance immunoregulation improved in vivo microbiota mortality nanobodies neutravidin novel overexpression prevent problem drinker programmed cell death ligand 1 standard care uptake wound healing

项目摘要

Project Summary Liver fibrosis is a wound healing process characterized by the accumulation of excess extracellular matrix (ECM) in the liver. 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. If left untreated, liver fibrosis will develop into liver cirrhosis, which is irreversible and affects nearly 633,233 adults in the United States. Unfortunately, there is no standard treatment for liver fibrosis till now. Therefore, effective antifibrotic medicines are needed urgently The accumulation of type I collagen in fibrotic liver is primarily due to an increase in the half-life of its mRNA in activated hepatic stellate cells (HSCs). We recently demonstrated that blocking PCBP2 expression using siRNA can efficiently decrease the stability of the collagen α1(I) mRNA and subsequently reverse alcohol- and cytokine-induced fibrogenesis in HSCs. We also discovered an IGF2R-specific peptide that can be used to specifically deliver cargos to activated HSCs. We will improve our current nanocomplex system to enhance the delivery of the PCBP2 siRNA to activated HSCs. It has been well established that the activation and proliferation of HSCs is the central event in liver fibrogenesis. Recently, experimental and clinical studies have shown that inducing apoptosis of activated HSCs in fibrotic liver is a rational and potential anti-fibrotic approach. It was found that HSCs inhibit T cells and B cells through PD-L1 on the surface of HSCs. PD-L1 is overexpressed in activated HSCs, leading to the strong immune modulatory activity of the activated HSCs against T-cell response. Activated HSCs exert inhibitory effects on infiltrating CD8+ T cells and induction effects on CD4+CD25+ regulatory T (Treg) cells. The immune modulatory activity of activated HSCs can be reversed by anti- PD-L1 antibodies to block the PD-1/PD-L1 interaction. We therefore hypothesize that anti-PD-L1 inhibitor can be utilized to restore the activity of infiltrating T cells in the fibrotic liver to clear activated HSCs which overexpress PD-L1. Our strategy is to develop a combination therapy to reverse the accumulated type I collagen using PCBP2 siRNAs and induce apoptosis of activated HSCs using PD-L1 inhibitors. Our central hypothesis is that alcoholic liver fibrosis can be reversed by targeting two different key steps in liver fibrogenesis.

项目总结