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

描述（由申请人提供）：该项目将发现和测试新的化合物作为潜在的治疗药物，以及测试和发现信号通路作为潜在的调节剂，由¿1-抗胰蛋白酶缺乏症（ATD）引起的肝脏疾病，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。这个项目产生了4种合作：博士之间的合作。Perlmutter、Michalopoulos和Stolz研究表明，卡马西平通过增强突变ATZ的自噬降解，可以减少ATD小鼠PiZ模型中肝脏ATZ负荷和纤维化，从而证明内源性蛋白酶抑制机制可以作为治疗的靶点；Silverman博士和Perlmutter博士之间的合作使用了新开发的秀丽隐杆线虫ATD模型和高含量筛选平台，为发现其他药物和修饰剂提供了强大的引擎；博士之间的合作。Bahar， Silverman和Perlmutter为ATD的潜在药物发现增加了计算药理学策略；博士之间的合作。Fox， Chowdhury和Perlmutter已经证明，移植的肝细胞将重新填充ATD的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的个性化医疗。这4个项目包括：1)在哺乳动物细胞系和小鼠ATD模型中测试新的药物和修饰物候选物（Pl-Perlmutter）；2)利用秀丽隐杆线虫ATD模型发现新的药物和修饰剂（Pl-Silverman）；3)利用复杂的病理和基因组方法阐明ATD小鼠模型中肝细胞过度增殖的机制（Pl-Michalopoulos）；4)利用新的免疫缺陷PiZ小鼠模型和iPS细胞系进行再种群研究，以开发具有宿主特异性修饰剂的ATD模型“人源化”小鼠（co- pi: Fox; Chowdhury）。S核包括：A)细胞和组织成像（Pl- Stolz）；B)计算药理学（Pl-Bahar）；C) Genomics （Pi-Bell）。这组杰出的研究人员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，病理和基因组技术，将为ATD带来新的药物和可药物靶点。

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.