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

描述（由申请人提供）：随着世界老龄化人口的迅速增加，迫切需要一种治疗神经退行性疾病的方法。阿尔茨海默病（AD）是老年人最常见的记忆疾病，每年摧毁数百万人的思想。过去十年的研究表明，淀粉样蛋白肽，可溶性毒素，在阿尔茨海默病的发病机制中起着核心作用。然而，尽管我们越来越了解阿尔茨海默病是如何破坏大脑的，但目前还没有有效的治疗方法来预防或改变这种疾病的进程。该建议旨在确定和开发针对AD的神经保护策略。我们建议研究胶原蛋白VI的新功能，一种细胞外基质蛋白，在保护大脑免受A¿的有害影响。我们的初步研究表明，胶原VI在阿尔茨海默病小鼠模型和人类阿尔茨海默病小鼠大脑中显著增加，可显著阻止a¿对小鼠神经元的毒性。为了扩展这些发现，在特异性目标1中，我们将研究胶原VI的细胞外作用，目的是确定胶原VI是否与A¿结合，改变其组装，并增强淀粉样斑块的形成。在Specific Aim 2中，我们将研究胶原VI介导的细胞内保护机制，以确定胶原VI是否会改变关键生存因子的表达以对抗A¿毒性。在Specific Aim 3中，我们将重点关注胶原VI对行为的影响，并确定胶原VI是否能预防A依赖型认知功能障碍。我们的研究可能揭示了关键的保护机制，可以作为开发治疗AD和其他衰老疾病的直接靶点。该候选人是一名内科科学家，致力于学术医学的职业生涯，专注于确定预防老年神经退行性疾病（如阿尔茨海默病和相关痴呆症）的策略。该候选人拥有神经科学博士学位和医学博士学位，并接受过神经病学临床培训和痴呆症专科培训。研究计划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方面的培训基础上，为阿尔茨海默病的转基因小鼠模型、行为分析、组织学、细胞培养和病毒载体提供专业知识。提案中描述的指导和研究经验将提供资源和薪水。

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.