New Therapies for Liver Fibrosis and Hyperproliferation in Alpha1-AT Deficiency

治疗 Alpha1-AT 缺乏症肝纤维化和过度增殖的新疗法

• 批准号: 10197888
• 负责人: David H Perlmutter
• 金额: $ 190.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197888
• 关键词: Biological Models; Caenorhabditis elegans; Carbamazepine; Carcinoma; Cell Line; Cell Transplantation; Cirrhosis; Collaborations; FDA approved; Fibrosis; Foxes; Genetic; Genome engineering; Genomics; Goals; Hepatic; Hepatocyte; Hepatocyte transplantation; Human; Immune; Knowledge; Liver; Liver Fibrosis; Liver diseases; Mammalian Cell; Modeling; Pathologic; Pharmaceutical Preparations; Pharmacology; Phenothiazines; Phenotype; Research Personnel; Signal Pathway; Techniques; Testing; Therapeutic Agents; Tissue imaging; Variant; alpha 1-Antitrypsin Deficiency; cellular imaging; disease phenotype; drug discovery; druggable target; effective therapy; humanized mouse; induced pluripotent stem cell; liver transplantation; mouse model; mutant; new therapeutic target; novel; novel therapeutics; personalized medicine; programs; proteostasis; screening; targeted treatment; tool

Project Summary This program project will discover and test novel compounds as potential therapeutic agents, as well as test and discover signaling pathways as potential modifiers, of liver disease due to α1antitrypsin deficiency (ATD), one of the most common genetic causes of liver disease and a frequent indication for liver transplantation. The program project grew out 4 collaborations: collaboration between Drs Perlmutter and Silverman showed that, by enhancing autophagic degradation of mutant ATZ, carbamazepine and phenothiazines could reduce hepatic ATZ load and fibrosis in the PiZ mouse model of ATD, and therein provided evidence that endogenous proteostasis mechanisms could be targeted for therapeutics; collaboration between Drs Silverman and Perlmutter using a newly developed C. elegans model of ATD and a high-content screening platform generated a powerful engine for discovery of additional drugs and modifiers; collaboration between Drs Bahar, Silverman and Perlmutter has added computational pharmacological strategies to potential drug discovery for ATD; collaboration between Dr. Fox and Perlmutter has shown that transplanted hepatocytes will re-populate the liver of the PiZ mouse model of ATD and that iPS-derived hepatocytes (iHeps)can model personalized variations in the liver disease phenotype of ATD, providing the basis for use of iHeps for `humanized' mouse models of ATD with the ultimate goal of personalized medicine for ATD. The 3 projects include: 1) testing of novel drug and genetic modifier candidates in mammalian cell line and mouse models of ATD (PI-Perlmutter); 2) use of the C. elegans model of ATD to discover new drugs and modifiers (PI-Silverman); 3) repopulation studies using a new immune- deficient PiZ mouse model and iPS cell lines to develop `humanized' mice that model ATD together with host-specific modifiers (PI: Fox). The 3 cores include: A) Cell and Tissue Imaging (PI- Fitzpatrick); B) Computational Pharmacology (PI-Bahar); C) Genome Engineering (PI-Milbrandt). This outstanding group of investigators will use existing and develop novel model systems which together with sophisticated drug discovery tools, pathologic and genomic techniques will lead to new drugs and druggable targets for ATD.

项目概要 该计划项目将发现和测试作为潜在治疗剂的新化合物，并测试 并发现信号通路作为 α1 抗胰蛋白酶缺乏症 (ATD) 引起的肝脏疾病的潜在调节剂， 肝病最常见的遗传原因之一，也是肝移植的常见指征。 该计划项目产生了 4 项合作：Perlmutter 博士和 Silverman 之间的合作表明 通过增强突变 ATZ 的自噬降解，卡马西平和吩噻嗪可以减少 PiZ 小鼠 ATD 模型中肝脏 ATZ 负荷和纤维化的变化，并提供了内源性证据 西尔弗曼博士和他的合作可以针对蛋白质稳态机制进行治疗； Perlmutter 使用新开发的 ATD 线虫模型和生成的高内涵筛选平台 巴哈尔博士和西尔弗曼博士之间合作的强大引擎，用于发现其他药物和修饰剂； Perlmutter 为 ATD 的潜在药物发现添加了计算药理学策略； Fox 博士和 Perlmutter 之间的合作表明，移植的肝细胞将重新填充肝脏 ATD 的 PiZ 小鼠模型以及 iPS 衍生的肝细胞 (iHeps) 可以模拟 ATD 的个性化变异 ATD 的肝病表型，为使用 iHeps 构建 ATD“人源化”小鼠模型提供了基础 以针对 ATD 的个性化医疗为最终目标，这 3 个项目包括：1）新药和药物的测试。 哺乳动物细胞系和 ATD 小鼠模型中的遗传修饰候选物 (PI-Perlmutter) 2) C. ATD 线虫模型用于发现新药物和修饰剂 (PI-Silverman) 3) 使用新方法进行再种群研究； 免疫缺陷 PiZ 小鼠模型和 iPS 细胞系共同开发模拟 ATD 的“人源化”小鼠 具有宿主特异性修饰符（PI：Fox），这 3 个核心包括：A）细胞和组织成像（PI-Fitzpatrick）； 计算药理学（PI-Bahar）；C）基因组工程（PI-Milbrandt）。 研究人员将使用现有的并开发新颖的模型系统，该系统与复杂的药物一起 发现工具、病理学和基因组技术将带来 ATD 的新药和药物靶标。