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

了解 ECSIT 在神经退行性疾病和阿尔茨海默病中的作用

• 批准号: 10216433
• 负责人: OTTAVIO ARANCIO
• 金额: $ 68.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216433
• 关键词: AD transgenic mice; Affect; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animals; Appearance; Architecture; Attenuated; Autophagocytosis; Autopsy; Behavior; Biology; Brain; Calcium; Cells; Cognitive; Cognitive deficits; Collaborations; Complex; Data; Defect; Dementia; Developed Countries; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Etiology; Event; Exhibits; Functional disorder; Generations; Genetic Determinism; Homeostasis; Human; Impairment; Incidence; Laboratories; Lead; Link; Longevity; LoxP-flanked allele; Memory impairment; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mouse Strains; Mus; Mutation; Names; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; New York; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Pharmacology; Phenotype; Physiological; Play; Predisposition; Principal Investigator; Production; Proteins; Quality Control; Reactive Oxygen Species; Regulation; Research; Role; Sampling; Series; Societies; Susceptibility Gene; Swedish mutation; Symptoms; Synapses; System; Testing; Therapeutic; Transgenic Organisms; age related; catalase; cell injury; cell motility; cohort; cost; experimental study; insight; macrophage; mitochondrial dysfunction; mouse model; neuron loss; neuropathology; oxidative damage; presenilin-1; respiratory; stressor; tau Proteins; uptake

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.

项目概要 尽管进行了大量研究，但阿尔茨海默病（AD）是人类最常见的痴呆症。 迄今为止，AD 尚无治愈方法，而且发达国家 AD 发病率不断上升，给人们带来了巨大的代价 随着寿命的增加，AD 有两种形式，它们具有遗传决定因素并包括 大约 5% 的病例，以及那些零星发生的病例，特别是在老龄化过程中，并且包括大量病例 大多数（约 95%）的新 AD 病例诊断出散发性 AD 的潜在诱因多种多样，而且效果并不明显。 目前的治疗策略仅限于减轻 AD 症状而不影响的策略。 因此，了解疾病的病因对于产生疾病本身是必要的。 一种被广泛接受的假说，称为“线粒体级联假说”，认为 衰老导致受损线粒体积累，产生线粒体活性氧 (mROS)，引发进行性氧化损伤，最终导致 AD 的发展。 经过数十年的研究，mROS 或受损线粒体异常积累的明确证据是关键 我们的初步研究尚未确定线粒体复合物 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 此外，我们还获得了表明 AD 中 ECSIT 表达/功能失调的证据。 因此，我们提出了一系列利用两位校长独特专业知识的实验 研究人员和机构能力，以充分描述 ECSIT 在神经变性和 AD 中的作用。 所提出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 发展之间的关系。