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

项目摘要 该计划项目将发现和测试新的化合物作为潜在的治疗药物，以及测试 并发现信号通路作为潜在的调节剂，由于α 1抗胰蛋白酶缺乏症（ATD）引起的肝病， 肝脏疾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个合作：Perlmutter博士和Silverman博士之间的合作显示， 通过增强突变ATZ的自噬降解，卡马西平和吩噻嗪可以减少 在ATD的PiZ小鼠模型中，肝ATZ负荷和纤维化，并且其中提供了内源性 蛋白质抑制机制可以作为治疗的靶点;西尔弗曼博士和 Perlmutter使用新开发的C. elegans模型的ATD和高内容筛选平台生成 一个强大的引擎，用于发现其他药物和修饰剂;巴哈尔博士和西尔弗曼博士之间的合作 Perlmutter为ATD的潜在药物发现增加了计算药理学策略; Fox博士和Perlmutter的合作表明，移植的肝细胞将重新填充肝脏 以及iPS衍生的肝细胞（iHep）可以模拟ATD的PiZ小鼠模型的个性化变化， ATD的肝脏疾病表型，为使用iHep作为ATD的“人源化”小鼠模型提供了基础 最终的目标是为ATD提供个性化的治疗。这3个项目包括：1）新药试验， 在哺乳动物细胞系和ATD小鼠模型中的遗传修饰剂候选物（PI-Perlmutter）; 2）使用C. elegans ATD模型，以发现新的药物和修饰剂（PI-Silverman）; 3）使用新的 免疫缺陷PiZ小鼠模型和iPS细胞系以开发一起模拟ATD的“人源化”小鼠 用宿主特异性修饰剂（PI：Fox）。3个核心包括：A）细胞和组织成像（PI-菲茨帕特里克）; B） 计算药理学（PI-Bahar）; C）基因组工程（PI-Milbrandt）。这批获奖的杰出 研究人员将使用现有的和开发新的模型系统， 发现工具、病理学和基因组技术将为扶贫国际运动带来新的药物和药物靶点。

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.