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

项目总结 阿尔茨海默病(AD)是人类最常见的痴呆症。尽管进行了密集的研究，但仍有 到目前为止，阿尔茨海默病还没有治愈方法，发达国家阿尔茨海默病的发病率不断上升，这给 随着寿命的延长，社会也在不断增加。AD有两种形式，一种是具有遗传决定因素的，另一种是包括 约5%的病例，以及那些零星出现的病例，特别是在衰老后出现的病例，构成了巨大的 大多数(~95%)新发AD病例确诊。散发性AD的潜在诱因是多样的，而且不是很好 明白了。目前的治疗策略仅限于那些缓解AD症状而不影响 疾病本身的发展。因此，了解疾病的病因是必要的，以产生 更好的治疗方法。一个被广泛接受的假说，也就是所谓的线粒体级联假说，认为 衰老会导致受损的线粒体积累，从而产生线粒体活性氧物种 (MROS)，触发渐进性氧化损伤，最终导致AD的发展。然而，尽管 几十年的研究，MRO或受损线粒体异常堆积的确凿证据是关键 触发因素尚未出现。我们的初步研究确定了线粒体复合体I的关键作用 组装因子ECSIT对线粒体功能、MRO产生和线粒体质量的调节 控制力。此外，我们还获得了在AD中涉及ECSIT表达/功能失调的证据。 因此，我们提出了一系列实验，利用这两位校长的独特专业知识 研究人员和机构能力，以充分描述ECSIT在神经退行性变和AD中的作用。 拟议的实验将使我们能够在小鼠模型中直接测试线粒体级联假说。 并探讨ECSIT失调与AD发生发展的关系。

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.