Treating AT Deficiency with Drugs that Modulate the Proteostasis Network

项目摘要 经典型α 1-抗胰蛋白酶缺乏症（ATD）是肝病最常见的遗传病因之一。 肝移植是目前唯一可用的治疗方法。与ATD相关的肝脏疾病 特征在于导致肝硬化和肝细胞过度增殖的典型慢性纤维化， 易患肝癌这种病理学归因于功能获得、蛋白毒性效应 在肝细胞的内质网（ER）中积累的突变AT Z。我的实验室已经阐明了 肝细胞科普ATZ在ER中蓄积的蛋白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、NFκB、ER-和β-半胱氨酸蛋白酶， 未折叠的蛋白质反应）。我们的工作假设是，药理学策略，利用 这些天然存在的、推测为保护性的蛋白质稳态调节机制将具有治疗作用， 对ATD引起的肝脏疾病的影响。最近，我们证实了这一假设， 自噬增强剂卡马西平（CBZ）可促进ATZ降解，降低肝脏ATZ负荷 和肝纤维化。在这里提出的工作中，我们将进一步探讨这一假设 通过研究其他对自噬系统具有特定作用的候选药物，包括 FDA批准的药物，环糊精和粘脂激动剂。该项目还将利用C。elegans 基于ATD模型的高内涵筛选平台（项目2）与计算药理学 分析（核心B）以发现其他治疗候选物。最后，我们将研究几个序列 作为由独特家族的全外显子组测序产生的候选遗传修饰剂的变体， 队列人群。将在模型系统（项目3，核心A和C）中测试这些变体的有效性， 有望进入诊断平台，并作为药物开发的新靶点， 最先进的个性化医疗方法。

Project Summary The classical form of α1antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease. Liver transplantation represents the only treatment currently available. 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 gain-of-function, proteotoxic effect of mutant AT Z that accumulates in the endoplasmic reticulum (ER) of liver cells. 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, NFκB, 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. In the work proposed here we will pursue this hypothesis further by investigating other drug candidates with putative actions specifically on the autophagy system, including FDA-approved drugs, cyclodextrins and mucolipin agonists. The project will also capitalize on a C. elegans ATD model-based high content screening platform (Proj 2) together with computational pharmacological analyses (core B) to discover additional therapeutic candidates. Finally, we will investigate several sequence variants that are candidate genetic modifiers arising from whole exome sequencing of a unique family and cohort populations. These variants will be tested for validity in model systems (Proj 3, Cores A and C), hopefully to move into diagnostic platforms and as novel targets for drug development that would enable state- of-the art personalized medicine approaches.