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

项目概要： α1-抗胰蛋白酶缺乏症（ATD）肝病是最常见的遗传性肝病之一 儿童和成人。目前唯一可用的治疗方法是肝移植。的病理生物学 肝脏疾病始于α1-抗胰蛋白酶（AT）的点突变，AT是肝脏中最丰富的分泌性蛋白酶之一， 肝脏的糖蛋白。变体α1-抗胰蛋白酶Z（ATZ）易于错误折叠，导致其 在肝细胞分泌途径的早期积累。大多数ATZ在 内质网（ER）作为聚合物和聚集体，我们现在知道，这是这种积累， 一种聚合性、易聚集的ATZ，通过毒性获得功能启动肝损伤过程 机制关于ATZ蓄积后导致肝脏损害的病理生物学步骤知之甚少。 损伤，但假设肝细胞功能受损，具有典型的纤维化后果。 在人类ATD患者和PiZ的肝细胞中观察到线粒体的显着变化 小鼠ATD模型，导致推测线粒体功能障碍至少是ATD的最后步骤的一部分。 肝细胞功能的死亡是严重ATD肝病的特征。 多年来，我们已经了解到，只有一个亚组的纯合子为ATZ发展进行性 肝脏疾病和大多数完全逃脱临床影响。这一观察使人们认识到， 遗传和环境修饰剂在ATZ的病理生物学效应中起重要作用。工作导致 Perlmutter实验室的研究表明，细胞内的降解途径，即自噬是一个关键， 肝细胞中ATZ积累决定因素和增强ATZ自噬降解的药物 ATZ在动物模型（包括ATZ线虫和PiZ小鼠模型）中降低肝纤维化。其他 最近的研究已经显示了对参与特定细胞器的自噬的分子途径的特异性， 术语“ER-吞噬”最近被认为至少是ATZ被 特别是降解。此外，一项非常重要的新研究表明，至少有一种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肝脏疾病病理学的关键部分，在两个方面， 细胞能量代谢和减少的自噬反应，并且其中线粒体功能是非常重要的 潜在治疗干预的吸引人的目标。在这项资助中，我们建议调查的影响， ATZ积累对线粒体功能的影响，以更好地了解肝脏受损的机制 并研究线粒体功能是否可以作为治疗的靶点。 我们这些研究的总体目标是为人类ATD肝脏的临床试验提供基础 针对线粒体功能障碍的疾病。

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.