New therapies for liver fibrosis and hyperproliferation in alpha1-AT deficiency

描述（由申请人提供）：该计划项目将发现和测试新型化合物作为潜在的治疗药物，以及测试和发现信号通路作为潜在的调节剂，由于1-抗胰蛋白酶缺乏症（ATD），肝病最常见的遗传原因之一，也是肝移植的常见指征。该项目产生了4个合作：Perlmutter博士，Michalopoulos博士和Stolz博士之间的合作表明，通过增强突变ATZ的自噬降解，卡马西平可以减少ATD PiZ小鼠模型中的肝ATZ负荷和纤维化，并提供证据表明内源性蛋白质稳态机制可以作为治疗的靶点; Drs Silverman和Perlmutter博士之间的合作使用新开发的C. elegans ATD模型和高内涵筛选平台为发现其他药物和修饰剂提供了强大的引擎; Bahar博士、Silverman博士和Perlmutter博士之间的合作为ATD的潜在药物发现增加了计算药理学策略; Fox、Chowdhury和Perlmutter博士之间的合作表明，移植的肝细胞将重新填充ATD PiZ小鼠模型的肝脏，为开发ATD的“人源化”小鼠模型提供了潜力，最终目标是ATD的个性化药物。这4个项目包括：1）在ATD的哺乳动物细胞系和小鼠模型（P1-Perlmutter）中测试新的药物和修饰剂候选物; Elegans ATD模型以发现新的药物和修饰剂（Pl-Silverman）; 3）使用复杂的病理学和基因组方法来阐明ATD小鼠模型中肝细胞过度增殖的机制（Pl-Michalopoulos）; 4）使用新的免疫缺陷PiZ小鼠模型和iPS细胞系进行再增殖研究，以开发与宿主特异性修饰剂一起模拟ATD的“人源化”小鼠（co-PI：Fox; Chowdhury）。S核心包括：A）细胞和组织成像（Pl- Stolz）; B）计算药理学（Pl-Bahar）; C）基因组学（Pi-Bell）。这个杰出的研究小组将利用现有的和开发新的模型系统，与先进的药物发现工具，病理和基因组技术一起，将导致新的药物和药物治疗ATD的目标。

DESCRIPTION (provided by applicant): 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 ¿1-antitrypsin 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, Michalopoulos and Stolz showed that, by enhancing autophagic degradation of mutant ATZ, carbamazepine 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 Drs. Fox, Chowdhury and Perlmutter has shown that transplanted hepatocytes will re-populate the liver of the PiZ mouse model of ATD, providing the potential for developing 'humanized' mouse models of ATD with the ultimate goal of personalized medicine for ATD. The 4 projects include: 1) testing of novel drug and modifier candidates in mammalian cell line and mouse models of ATD (Pl-Perlmutter); 2) use of the C. elegans model of ATD to discover new drugs and modifiers (Pl-Silverman); 3) use of sophisticated pathologic and genomic approaches to elucidate mechanisms of hepatocyte hyperproliferation in mouse models of ATD (Pl-Michalopoulos); 4) repopulation studies using a new immunedeficient PiZ mouse model and iPS cell lines to develop 'humanized' mice that model ATD together with host-specific modifiers (co-PIs: Fox; Chowdhury). The S cores include: A) Cell and Tissue Imaging (Pl- Stolz); B) Computational Pharmacology (Pl-Bahar); C) Genomics (Pi-Bell). 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.