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

描述(申请人提供)：随着世界老龄化人口的迅速增加，迫切需要治疗神经退行性疾病。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大脑。过去十年的研究表明，淀粉样多肽(A)是一种可溶性毒素，在AD的发病机制中发挥着核心作用。然而，尽管我们越来越多地了解阿尔茨海默病是如何破坏大脑的，但没有有效的治疗方法来预防或改变疾病的进程。这项建议旨在确定和开发针对AD的神经保护策略。我们建议研究细胞外基质蛋白VI型胶原的新功能，以保护大脑免受A？的有害影响。我们的初步研究表明，在阿尔茨海默病小鼠模型和人类阿尔茨海默病模型中大脑中显著增加的VI型胶原蛋白，极大地防止了Aβ对小鼠神经元的毒性。为了扩大这些发现，在特定的目标1中，我们将研究VI型胶原的细胞外作用，目的是确定VI型胶原是否与A结合，改变其组装，并促进淀粉样斑块的形成。在特定的目标2中，我们将研究VI型胶原介导的保护作用的细胞内机制，以确定VI型胶原是否改变关键生存因子的表达以对抗A型毒性。在具体目标3中，我们将重点研究VI型胶原对行为的影响，并确定VI型胶原是否能预防A？依赖的认知功能障碍。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。应聘者是一名内科科学家，坚定地致力于学术医学的职业生涯，专注于确定预防衰老引起的神经退行性疾病的策略，如阿尔茨海默病和相关痴呆症。应聘者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方面的培训基础上，以提供阿尔茨海默病转基因小鼠模型、行为分析、组织学、细胞培养和病毒载体方面的专业知识。提案中所述的指导和研究经验将提供资源、工资。 相关性：尽管阿尔茨海默病(AD)摧毁了数百万人的心灵，但没有真正有效的治疗方法。这项建议旨在通过研究新发现的VI型胶原蛋白的保护作用来开发保护大脑免受AD影响的策略，VI型胶原蛋白在大脑中的作用几乎是未知的。这种保护机制可能是开发有效的AD治疗的直接靶点。

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.