Collagen VI: Novel Mechanisms and Functions in Alzheimer's Disease

描述（由申请人提供）：随着世界人口老龄化的迅速增加，迫切需要治疗神经退行性疾病。阿尔茨海默氏病（AD）是老年人最常见的记忆障碍性疾病，每年都会使数百万人的大脑出现问题。过去十年的研究表明，淀粉样蛋白（A）肽，可溶性毒素，在AD的发病机制中发挥着重要作用。然而，尽管我们越来越了解AD如何影响大脑，但没有有效的治疗方法来预防或改变疾病的进程。该提案旨在确定和开发针对AD的神经保护策略。我们建议研究VI型胶原蛋白（一种细胞外基质蛋白）在保护大脑免受A？有害影响方面的新功能。我们的初步研究表明，在AD小鼠模型和人类AD中大脑中强烈增加的胶原VI显着防止A？在小鼠神经元中的毒性。为了扩展这些发现，在特定目标1中，我们将检查胶原VI的细胞外作用，目的是确定胶原VI是否结合A？，改变其组装，并增强淀粉样斑块形成。在特定目标2中，我们将研究胶原VI介导的保护的细胞内机制，以确定胶原VI是否改变关键存活因子的表达以对抗A？毒性。在具体目标3中，我们将重点关注胶原VI对行为的影响，并确定胶原VI是否可以预防A？依赖性认知功能障碍。我们的研究可能揭示关键的保护机制，可以作为开发AD和其他衰老疾病治疗的直接靶点。候选人是一名医生兼科学家，致力于学术医学的职业生涯，专注于确定预防衰老神经退行性疾病（如阿尔茨海默病和相关痴呆症）的策略。候选人拥有神经科学博士学位和医学博士学位，并接受过神经学临床培训和痴呆症专科培训。研究提案和职业发展计划建立在她在神经科学，衰老和神经退行性疾病的培训，提供阿尔茨海默病，行为分析，组织学，细胞培养和病毒载体的转基因小鼠模型的专业知识。建议书中所述的指导和研究经验将提供资源、薪金和其他福利。 相关性：尽管阿尔茨海默病（AD）困扰着数百万人的大脑，但目前还没有真正有效的治疗方法。该提案旨在通过研究新发现的胶原VI的保护作用来开发保护大脑免受AD的策略，胶原VI是一种在大脑中的作用几乎未知的蛋白质。这种保护机制可能是开发有效AD治疗的直接目标。

DESCRIPTION (provided by applicant): With the rapid increase in the world's aging population, a cure for neurodegenerative conditions is urgently needed. Alzheimer's disease (AD), the most common disease of memory in the elderly, devastates the minds of millions of people every year. Research over the past decade has revealed that amyloid-¿ (A¿) peptides, soluble toxins, play a central role in the pathogenesis of AD. However, despite our growing knowledge of how AD devastates the brain, there are no effective treatments to prevent or modify the course of the disease. This proposal is aimed at identifying and developing neuroprotective strategies against AD. We propose to investigate novel functions of collagen VI, an extracellular matrix protein, in protection against the deleterious effects of A¿ in the brain. Our preliminary studies show that collagen VI, which is robustly increased in the brain in a mouse model of AD and in human AD, dramatically prevents the toxicity of A¿ in mouse neurons. To extend these findings, in Specific Aim 1, we will examine the extracellular actions of collagen VI, with the goal of determining whether collagen VI binds A¿, alters its assembly, and enhances amyloid plaque formation. In Specific Aim 2, we will investigate intracellular mechanisms of collagen VI- mediated protection to determine whether collagen VI alters the expression of key survival factors to counter A¿ toxicity. In Specific Aim 3, we will focus on the effects of collagen VI on behavior and ascertain whether collagen VI prevents A¿-dependent cognitive dysfunction. Our studies may reveal key protective mechanisms that could serve as direct targets for the development of treatments for AD and other diseases of aging. The candidate is a physician-scientist with a strong commitment to a career in academic medicine focused on identifying strategies to protect against neurodegenerative conditions of aging, such as Alzheimer's disease and related dementias. The candidate has a PhD in neuroscience and an MD with clinical training in neurology and subspecialty training in dementias. The research proposal and career development plan build upon her training in neuroscience, aging, and neurodegenerative conditions to provide expertise in transgenic mouse models of Alzheimer's disease, behavioral analysis, histology, cell culture and viral vectors. The mentoring and research experience described in the proposal would provide resources, salary. RELEVANCE: Although Alzheimer's disease (AD) devastates the minds of millions of people, there are no truly effective treatments. This proposal is aimed at developing strategies to protect the brain against AD by investigating newfound protective actions of collagen VI, a protein whose effects in the brain are virtually unknown. The mechanisms of this protection may be direct targets for developing effective AD treatments.