Understanding the role of ECSIT in neurodegeneration and Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是人类最常见的痴呆形式。尽管有大量的研究， 目前还没有治愈AD的方法，而发达国家AD发病率的增加给人们带来了巨大的成本， 社会随着寿命的增长。存在两种形式的AD，具有遗传决定因素并且包括 大约5%的病例，以及那些偶尔出现的病例，特别是在衰老时， 大多数（约95%）新发AD病例确诊。散发性AD的潜在触发因素多种多样， 明白目前的治疗策略仅限于那些减弱AD病理学而不影响 疾病本身的发展。因此，了解疾病的病因是必要的， 更好的治疗方法一个被广泛接受的假说，被称为“线粒体级联假说”，假定， 衰老导致产生线粒体活性氧的受损线粒体的积累 （mROS），引发最终导致AD发展的进行性氧化损伤。但尽管 几十年的研究，明确的证据表明，mROS或受损线粒体的异常积累是关键， 触发器没有出现。我们的初步研究确定了线粒体复合物I的关键作用， 组装因子ECSIT在调节线粒体功能、mROS产生和线粒体质量中的作用 控制此外，我们已经获得的证据表明，AD中ECSIT表达/功能失调。 因此，我们提出了一系列的实验，利用独特的专业知识，这两个主要的 研究人员和机构能力，以充分表征ECSIT在神经变性和AD中的作用。 拟议的实验将使我们能够直接测试小鼠模型中的线粒体级联假说 并探讨ECSIT失调与AD发病的关系。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia in humans. Despite intense research there is as yet no cure for AD and the increasing incidence of AD in developed countries poses a tremendous cost to society as lifespans increase. There are two forms of AD, those that have genetic determinants and comprise approximately 5% of cases, and those that arise sporadically, particularly upon aging, and comprise the vast majority (~95%) of new AD cases diagnosed. The underlying triggers for sporadic AD are diverse and not well understood. Current therapeutic strategies are limited to those that attenuate AD symptomology without affecting the progression of the disease itself. Thus understanding the etiology of the disease is necessary to generate better therapeutics. A widely accepted hypothesis, known as the ‘mitochondrial cascade hypothesis’, posits that aging leads to accumulation of damaged mitochondria that produce mitochondrial reactive oxygen species (mROS), triggering progressive oxidative damage that ultimately results in development of AD. However, despite decades of study, definitive evidence for mROS or aberrant accumulation of damaged mitochondria as a key trigger have not emerged. Our preliminary studies establish a critical role for the mitochondrial complex I assembly factor ECSIT in the regulation of mitochondrial function, mROS production, and mitochondrial quality control. Moreover, we have obtained evidence implicating dysregulation of ECSIT expression/function in AD. Therefore, we propose a series of experiments that leverage the unique expertise of the two principal investigators, and institutional capabilities, to fully characterize the role of ECSIT in neurodegeneration and AD. The proposed experiments will allow us to directly test the mitochondrial cascade hypothesis in murine models of AD and also probe the relationship between ECSIT dysregulation and the development of AD.