Treating AT deficiency with drugs that modulate the proteoatasis network

项目总结（见说明）：经典形式的抗胰蛋白酶缺乏症（ATD）是肝脏疾病最常见的遗传原因之一。肝移植是目前治疗ATD引起的严重肝脏疾病的唯一方法。与ATD相关的肝脏疾病的特征是典型的慢性纤维化，导致肝硬化和肝细胞过度增殖，易导致肝细胞癌。这种病理归因于突变ATZ在肝细胞内质网（ER）中积累的蛋白质毒性作用，这是突变ATZ的聚合倾向特有的毒性获得功能机制。我的实验室已经阐明了肝细胞应对ATZ在内质网中积累的蛋白质毒性作用的潜在机制，包括一组独特的细胞内降解途径（蛋白酶体和自噬）和一组独特的特异性激活的信号通路（自噬、NFKB、ER和线粒体半胱天冬酶，但不包括未折叠的蛋白质反应）。我们的工作假设是，利用这些自然发生的保护性蛋白质平衡调节机制的药理学策略将对ATD引起的肝脏疾病产生治疗作用。最近，我们通过在ATD小鼠模型中显示自噬增强药物卡马西平（CBZ）促进ATZ的降解，减少肝脏ATZ负荷和肝纤维化来验证这一假设。在本应用程序中提出的工作中，我们将通过研究其他候选药物来进一步研究这一假设，这些候选药物可能对自噬或蛋白酶体系统具有特定的作用，以及候选药物，如组蛋白去乙酰化酶抑制剂，这些候选药物可能通过对细胞转录组的广泛作用来影响蛋白酶平衡网络。该项目还将利用基于秀丽线虫ATD模型的高含量筛选平台以及计算药理学分析以发现额外的候选治疗方法。最后，我们将研究其他细胞反应途径，如NFKB信号、caspase 12、SIDT2和PIS激酶，在ATD的病理效应中的作用，以确定这些途径是否可以在未来用于新的治疗策略。

PROJECT SUMMARY (See instructions): The classical form of al antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease. Liver transplantation represents the only treatment currently available for severe liver disease due to ATD. The liver disease associated with ATD is characterized by a stereotypical chronic fibrosis leading to cirrhosis and hepatocyte hyper-proliferation that predisposes to hepatocellular carcinoma. This pathology is attributed to the proteotoxic effect of mutant AT Z that accumulates in the endoplasmic reticulum (ER) of liver cells, a gain-of-toxic function mechanism specific for the polymerogenic tendencies of mutant ATZ. My lab has elucidated the potential mechanisms by which liver cells cope with the proteotoxic effects of ATZ accumulation in the ER including a distinct set of intracellular degradation pathways (proteasomal and autophagic) and a distinct set of signaling pathways that are specifically activated (autophagy, NFKB, ER- and mitochondrial-caspases but not the unfolded protein response). Our working hypothesis is that pharmacological strategies which capitalize on these naturally occurring, presumably protective proteostasis regulatory mechanisms will have a therapeutic effect on the liver disease caused by ATD. Recently, we validated this hypothesis by showing that an autophagy enhancer drug , carbamazepine (CBZ), promotes degradation of ATZ, reduces the hepatic ATZ load and hepatic fibrosis in vivo in a mouse model of ATD. In the work proposed in this application we will pursue this hypothesis further by investigating other drug candidates with putative actions specifically on the autophagy or on the proteasomal system as well as drug candidates such as histone deacetylase inhibitors which may affect the proteostasis network by broad actions on the cellular transcriptome The project will also capitalize on a C. elegans ATD model-based high content screening platform together with computational pharmacological analyses to discover additional therapeutic candidates. Finally, we will investigate the role of other cellular response pathways, such as NFKB signaling, caspase 12, SIDT2 and PIS kinase, in the pathologic effects of ATD to determine whether these pathways could be exploited for novel therapeutic strategies in the future.