Novel Pharmacological Strategies for Liver Disease in Antitrypsin Deficiency

描述（由申请人提供）：经典形式的α 1-抗胰蛋白酶（AT）缺乏症是儿童肝脏疾病最常见的遗传原因，也使成人易患肝损伤。 在这种缺陷中，点突变使得肝分泌蛋白易于错误折叠和聚集。 突变蛋白，α 1-抗胰蛋白酶Z（ATZ），积累在内质网（ER）的肝细胞，引起炎症和致癌作用的获得毒性功能的机制。 研究人员现在知道，当这种突变蛋白在该隔室中积累时，ER的质量控制装置通过两种一般机制降解这种突变蛋白：蛋白酶体途径负责处置可溶性ATZ，自噬途径负责处置保留在ER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置途径无法处理突变蛋白负荷。 在本申请中，研究人员将使用新开发的AT缺乏症伴严重肝损伤的基因工程小鼠模型，检查一次性途径功能的药理学增强预防和改善AT缺乏症肝脏疾病的假设。 三个新的策略的初步证据，并将进一步检查使用一系列的临床前研究在小鼠模型中：刺激胰岛素信号通路，增强自噬处置ATZ通过TOR激酶独立的机制;通过FDA已经批准用于人类的药物刺激ATZ的自噬处置，并且似乎通过胰岛素非依赖性和TOR激酶起作用，独立机制;使用对ATZ具有特异性解聚作用的肽刺激ATZ的蛋白酶体降解。 本申请中提出的研究有可能快速进入目前仅适用于肝移植治疗的肝病的药理学策略的临床试验。 说明：本申请提出了三种新的药理学策略的临床前研究，用于预防或治疗与α 1-抗胰蛋白酶缺乏相关的慢性肝炎和肝细胞癌，这是儿童最常见的遗传性肝病。

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.