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

基本信息

批准号：
10629415
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
项目类别：
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/10629415
关键词：
AD transgenic mice Affect Aging Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Animals Appearance Architecture Attenuated Autophagocytosis Autopsy Behavior Biology Brain Calcium Cells Central Nervous System 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 Institution Laboratories Link Longevity LoxP-flanked allele Macrophage Memory impairment Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Mouse Strains Mus Mutation Names Nerve Degeneration Neurodegenerative Disorders Neurons New York Oxidation-Reduction Oxidative Stress Pathogenesis Pathology Pathway interactions Phenotype Physiological Play Predisposition Principal Investigator Production Proteins Quality Control Reactive Oxygen Species Regulation Research Respiration Respiratory Chain Role Sampling Series Societies Susceptibility Gene Swedish mutation Symptoms Synapses System Testing Therapeutic age related catalase cell injury cell motility cohort cost experimental study insight mitochondrial dysfunction mouse model neuron loss neuropathology oxidative damage pharmacologic presenilin-1 stressor tau Proteins transgene expression transgenic model of alzheimer disease uptake

项目摘要

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.

项目摘要阿尔茨海默氏病（AD）是人类痴呆症的最常见形式。尽管有深入的研究目前尚无广告的治疗方法，发达国家的AD发生率的增加构成了巨大的代价随着寿命的增加，社会。有两种形式的AD，具有遗传确定剂且完整的AD形式大约5％的病例，以及偶发出现的病例，尤其是在老化时，并包括疫苗大多数（〜95％）被诊断出来的新广告病例。零星广告的基础触发器是潜水员，不好理解齿。当前的治疗策略仅限于减弱AD症状的情况而不影响AD症状。疾病本身的进展。理解该疾病的病因是必要的更好的疗法。广泛接受的假设，称为“线粒体级联假设”，认为这是衰老导致产生线粒体活性氧的线粒体受损的积累（MROS），触发氧化的渐进性损害，最终导致AD的发展。但是，需求数十年的研究，MRO的明确证据或线粒体受损的异常积累作为关键扳机尚未出现。我们的初步研究确定了线粒体复合物I的关键作用用于调节线粒体功能，MROS产生和线粒体质量的组装因子ECSIT 控制。此外，我们获得了证据，该证据隐含了AD中ECSIT表达/功能失调的证据。因此，我们提出了一系列实验，以利用这两个校长的独特专业知识研究人员和机构能力充分表征ECSIT在神经变性和AD中的作用。提出的实验将使我们能够直接测试鼠模型中的线粒体级联假设 AD，还探究ECSIT失调与AD发展之间的关系。