Novel therapies that target mitochondrial dysfunction for treatment of a1-antitrypsin deficiency liver disease

项目总结： α1抗胰蛋白酶缺乏症肝病是肝病最常见的遗传病因之一 在儿童和成人中。目前唯一可用的治疗方法是肝移植。该病的病原学 肝病始于α1-抗胰蛋白酶(AT)的点突变，AT是最丰富的分泌物之一 肝脏的糖蛋白。α-1-抗胰蛋白酶Z(ATZ)变异体容易错误折叠，从而导致其 在肝细胞分泌途径的早期部分积聚。大部分ATZ积聚在 内质网(ER)作为聚合物和聚集体，我们现在知道它是这种积累的 多聚性、易聚集的ATZ，通过毒性功能增强而启动肝损伤过程 机制。对ATZ蓄积后导致肝脏的病理生物学步骤知之甚少 损害，但假设肝细胞功能受损，出现典型的纤维化后果。 在ATD患者和PIZ患者的肝细胞中观察到明显的线粒体改变 ATD小鼠模型，导致推测线粒体功能障碍至少是ATD最后步骤的一部分 肝细胞功能的丧失是严重的ATD肝病的特征。 多年来，我们已经了解到，只有ATZ的纯合子亚群才会发展为进行性 而大多数肝病则完全逃脱了临床效果。这一观察结果使人们认识到 遗传和环境修饰物在ATZ的病理生物学效应中起着重要作用。工作主导 Perlmutter实验室已经证明，细胞内的降解途径，即自噬是一个关键 ATZ在肝细胞中蓄积的决定因素和促进自噬降解的药物 ATZ可减少动物模型中的肝纤维化，包括ATZ线虫和PIZ小鼠模型。其他 最近的研究表明，参与特定细胞器自噬的分子途径具有特异性， 最近，人们已经认识到，这一术语至少是ATZ过程的一部分。 特别是降级了。此外，一项非常重要的新研究表明，至少有一条ER吞噬途径 受氧化磷酸化基因和线粒体功能的调节。 基于这些考虑和提案中描述的新的初步数据，我们现在认为 线粒体损伤是ATD肝病病理生物学的关键部分，在两个方面，肝脏受损 细胞能量代谢和自噬反应减弱，其中线粒体的功能是非常重要的 吸引潜在治疗干预的目标。在这笔赠款中，我们建议调查 ATZ对线粒体功能的影响以更好地了解肝脏损伤的机制 并研究线粒体功能是否可以作为治疗的靶点。 我们这些研究的首要目标是为人类ATD肝脏的临床试验提供基础。 以线粒体功能障碍为目标的疾病。

PROJECT SUMMARY: α1-antitrypsin deficiency (ATD) liver disease is one of the most common genetic causes of liver disease in children and adults. The only currently available treatment is liver transplantation. The pathobiology of the liver disease begins with a point mutation in α1-antitrypsin (AT), one of the most abundant secretory glycoproteins of the liver. The variant, α1-antitrypsin Z (ATZ), is prone to misfolding and that leads to its accumulation within the early part of the secretory pathway of liver cells. Most of the ATZ accumulates in the endoplasmic reticulum (ER) as polymers and aggregates, and we now know that it is this accumulation of polymerogenic, aggregation-prone ATZ that initiates the process of liver damage by a gain-of-toxic function mechanism. Very little is known about the pathobiological steps after accumulation of ATZ that result in liver damage but it is assumed that liver cell function becomes impaired with stereotypical fibrogenic consequences. Marked alterations of mitochondria have been observed in liver cells of human ATD patients and the PiZ mouse model of ATD, leading to speculation that mitochondrial dysfunction is at least part of the final steps in the demise of liver cell function that characterizes severe ATD liver disease. Over the years we have learned that only a sub-group of homozygotes for ATZ develop progressive liver disease and the majority completely escape clinical effects. This observation has led to the recognition that genetic and environmental modifiers play an important role in the pathobiological effects of ATZ. Work led by the Perlmutter laboratory has shown that the intracellular degradation pathway known as autophagy is a key determinant of ATZ accumulation in liver cells and that drugs which enhance the autophagic degradation of ATZ decrease hepatic fibrosis in animal models, including the ATZ nematode and PiZ mouse models. Other recent studies have shown specificity for the molecular pathways involved in autophagy of specific organelles, and the term `ER-phagy' has recently been recognized as at least part of the process by which ATZ is specifically degraded. Furthermore, a very important new study has shown that at least one ER-phagy pathway is regulated by oxidative phosphorylation genes and mitochondrial function. Based on these considerations and new preliminary data described in the proposal, we now believe that mitochondrial impairment is a key part of the pathobiology of ATD liver disease in two ways, impaired liver cell energy metabolism and reduced autophagic response, and, therein, that mitochondrial function is a very appealing target for potential therapeutic interventions. In this grant we propose to investigate the effects of ATZ accumulation on mitochondrial function to better understand the mechanism by which liver is damaged and to investigate whether mitochondrial function can be targeted for therapy. Our overarching goal with these studies is to provide a basis for clinical trials of human ATD liver disease that target mitochondrial dysfunction.