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

描述(由申请者提供)：该项目将发现和测试作为潜在治疗剂的新化合物，以及测试和发现作为潜在修饰物的信号通路，以治疗由1-抗胰蛋白酶缺乏症(ATD)引起的肝病，ATD是肝病最常见的遗传原因之一，也是肝移植的常见适应症。该计划项目形成了4项合作：Perlmutter博士、Michalopoulos博士和Stolz博士之间的合作表明，通过促进突变ATZ的自噬降解，卡马西平可以减少ATZ突变小鼠模型中的肝脏ATZ负荷和纤维化，并在其中提供证据，证明内源性蛋白稳定机制可以作为治疗的靶点；DRS Silverman和Perlmuter之间的合作使用新开发的ATD线虫模型和高含量筛选平台，为发现更多药物和修饰物产生了强大的引擎；Bahar博士、Silverman博士和Perlmuter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博士、Chowdhury博士和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“人性化”ATD小鼠模型提供了潜力，最终目标是为ATD提供个性化药物。这4个项目包括：1)在哺乳动物细胞系和ATD小鼠模型中测试新型候选药物和修饰物(Pl-Perlmutter)；2)利用线虫ATD模型发现新药和修饰物(Pl-Silverman)；3)使用尖端病理学和基因组学方法阐明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细胞系进行再繁殖研究，以建立同时带有宿主特异性修饰物的ATD模型的“人源化”小鼠(co-Pis：Fox；Chowdhury)。S的核心包括：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)。这一杰出的研究小组将利用现有的和开发新的模型系统，结合复杂的药物发现工具、病理学和基因组技术，将为ATD带来新药和可用药靶点。

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.