Novel Pharmacological Strategies for Liver Disease in Antitrypsin Deficiency

描述（由申请人提供）：经典形式的a1-抗胰蛋白酶（AT）缺乏症是儿童肝脏疾病最常见的遗传原因，也容易使成人肝脏受损。在这种缺陷中，点突变使肝脏分泌蛋白易于错误折叠和聚集。突变蛋白a1-抗胰蛋白酶Z （ATZ）在肝细胞内质网（ER）中积累，通过毒性获得功能机制引起炎症和致癌。研究人员现在知道，内质网的质量控制装置降解突变蛋白有两种一般机制：蛋白酶体途径负责处理可溶性ATZ，自噬途径负责处理保留在内质网中的不溶性聚集ATZ。据推测，突变ATZ的积累及其肝毒性作用反映了蛋白酶体和自噬处理途径无法处理突变蛋白负荷。在本研究中，研究人员将利用一种新开发的具有严重肝损伤的AT缺乏症小鼠基因工程模型，检验药理学增强一次性途径功能的假设，即预防和改善AT缺乏症的肝脏疾病。提出了三种新策略的初步证据，并将在小鼠模型中通过一系列临床前研究进一步验证：刺激胰岛素信号通路，通过不依赖TOR激酶的机制增强ATZ的自噬处置；已经被FDA批准用于人类的药物刺激ATZ的自噬处理，并且似乎通过胰岛素不依赖型和TOR激酶不依赖型机制起作用；使用对ATZ具有特定解聚作用的肽刺激ATZ的蛋白酶体降解。本应用程序中提出的研究有可能迅速进入目前仅适用于肝移植治疗的肝脏疾病的药理策略的临床试验。

DESCRIPTION (provided by applicant): The classical form of a1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children and also predisposes adults to liver damage. In this deficiency a point mutation renders a hepatic secretory protein prone to misfolding and aggregation. The mutant protein, a1-antitrypsin Z (ATZ), accumulates in the endoplasmic reticulum (ER) of liver cells, causing inflammation and carcinogenesis by a gain-of-toxic function mechanism. The investigators now know that there are two general mechanisms by which the quality control apparatus of the ER degrades this mutant protein when it accumulates in that compartment: the proteasomal pathway is responsible for disposal of soluble ATZ and the autophagic pathway is responsible for disposal of insoluble aggregated ATZ that is retained in the ER. Presumably the accumulation of mutant ATZ and its hepatotoxic effects reflect an inability of proteasomal and autophagic disposal pathways to handle the mutant protein load. In this application the investigators will examine the hypothesis that pharmacological enhancement of the function of the disposable pathways prevents and ameliorates the liver disease of AT deficiency using a newly developed genetically engineered mouse model of AT deficiency with severe liver damage. Preliminary evidence for three novel strategies is presented and will be further examined using a series of preclinical studies in the mouse model: stimulation of the insulin signaling pathway that enhances autophagic disposal of ATZ through a TOR kinase-independent mechanism; stimulation of autophagic disposal of ATZ by drugs that are already approved for use in humans by the FDA and appear to work by insulin-independent and TOR kinase-independent mechanisms; stimulation of proteasomal degradation of ATZ using a peptide with a specific depolymerizing effect on ATZ. The studies proposed in this application have the potential to rapidly move into clinical trials of pharmacological strategies for a liver disease that is currently only amenable to liver transplantation therapy. NARRATIVE: This application proposes preclinical studies of three novel pharmacological strategies for preventing or treating chronic hepatitis and hepatocellular carcinoma associated with a1-antitrypsin deficiency, the most common genetic liver disease of children.