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潜在的治疗药物的新化合物，以及测试 并发现信号通路是α-1抗胰蛋白酶缺乏症引起的肝病的潜在修饰物， 这是肝脏疾病最常见的遗传原因之一，也是肝移植的常见适应症。 该计划项目产生了4个合作项目：DRS Perlmutter和Silverman之间的合作显示 通过促进突变型ATZ、卡马西平和吩噻嗪的自噬降解，可以减少 PIZ小鼠ATD模型中的肝ATZ负荷和肝纤维化，其中提供了内源性的证据 蛋白稳定机制可能成为治疗学的靶点；西尔弗曼博士和 Perlmuter使用新开发的ATD线虫模型和高含量筛选平台生成 发现更多药物和修饰剂的强大引擎；巴哈博士、西尔弗曼博士之间的合作 Perlmutter已经在ATD的潜在药物发现中增加了计算药理学策略； 福克斯博士和珀尔穆特博士的合作表明，移植的肝细胞将重新填充肝脏 PIZ小鼠ATD模型以及iPS来源的肝细胞(IHEPS)可以模拟个性化变异的ATD ATD的肝病表型，为将iHEPS用于ATD的人源化小鼠模型提供了基础 最终目标是为ATD提供个性化的药物。这3个项目包括：1)新药测试和 在哺乳动物细胞系和ATD小鼠模型中的候选遗传修饰物(PI-Perlmutter)；2)C. 发现新药和修饰剂的ATD的Elgans模型(PI-Silverman)；3)使用新的 免疫缺陷PIZ小鼠模型和iPS细胞系共同建立ATD模型的人源化小鼠 使用特定于主机的修改器(PI：FOX)。3个核心包括：A)细胞和组织成像(PI-Fitzpatrick)；B) 计算药理学(Pi-Bahar)；c)基因组工程(Pi-Milbrandt)。这一杰出的群体 研究人员将利用现有的和开发新的模型系统，与复杂的药物一起 发现工具、病理学和基因组技术将为ATD带来新的药物和可用药的靶点。

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.