The Role of Integrin Signaling Pathways in Alzheimer's Disease

描述（由申请人提供）： 项目总结/摘要：作为神经病理学领域的医生和科学家，我对大脑疾病，特别是与神经元功能障碍和变性相关的疾病有浓厚的兴趣。我的长期职业目标是了解一些最常见的神经退行性疾病（如阿尔茨海默病（AD））的分子机制，并将这些知识转化为临床相关的治疗方法。在我最近对神经发育的研究中，我发现了发育过程和神经退行性变之间的多种联系，我决定改变方向来探索这些联系。由于我以前没有在这个研究领域工作过，我设计了一个强化培训计划，以获得专业知识，并促进我过渡到这个重要的领域。Lennart Mucke博士是AD发病机制的主要权威，在他的指导下，我的研究计划将解决整合素信号通过改变淀粉样蛋白动力学和成熟神经元的谷氨酸受体运输在AD进展中起关键作用的假设。我将使用各种遗传学方法来改变培养细胞和小鼠模型中的整合素信号传导，并检查对神经毒性和淀粉样蛋白-2（A2）寡聚体的积累，聚集和内吞作用的影响。我也将评估改变整合素信号传导对A2介导的树突棘和突触形态学变化和谷氨酸受体定位的影响。作为这些研究的一部分，我将在整合素连接激酶（Ilk）缺失的背景下生成AD小鼠模型，并评估这些小鼠的斑块形成、突触功能、网络兴奋性和行为。Ilk介导了AD中涉及的大多数整合素异二聚体的功能，并且关注这种衔接蛋白将有助于广泛地调查整合素在AD中的功能。这项工作有望产生重要的见解基本生物学神经变性和整合素信号在成人大脑。此外，本提案旨在补充我之前的实验室经验，并为我提供成为独立研究者的技术和知识工具。格拉德斯通研究所和UCSF病理学系完全致力于提供所有必要的资源，以促进这项工作的成功完成。 公共卫生相关性： 项目叙述：目前还没有针对AD的疾病修饰疗法，迫切需要新的药物发现方法。整合素是AD药物发现工作的潜在新领域。特别是，整合素在认知功能中的作用表明，调节整合素信号传导可以延迟疾病过程早期神经元连接的丧失。我的研究有望揭示整合素在AD发病机制中的作用机制，并为未来的药物发现工作开辟道路。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT: As a physician-scientist in the field of neuropathology, I have a strong interest in diseases of the brain, particularly those associated with neuronal dysfunction and degeneration. My long-term career goal is to understand the molecular mechanisms that underlie some of the most common neurodegenerative diseases, such as Alzheimer's disease (AD), and to translate that knowledge into clinically relevant therapeutics. In my recent studies of neurodevelopment, I discovered multiple connections between developmental processes and neurodegeneration, and I decided to shift direction to explore those connections. Since I have not previously worked in this research area, I have designed an intensive training program to gain expertise and facilitate my transition to this important field. Under the mentorship of Dr. Lennart Mucke, a leading authority on AD pathogenesis, my research program will address the hypothesis that integrin signaling plays a critical role in the progression of AD by altering amyloid dynamics and glutamate receptor trafficking of mature neurons. I will use a variety of genetic methods to alter integrin signaling in cultured cells and mouse models and examine the resulting effects on neurotoxicity and the accumulation, aggregation and endocytosis of amyloid-2 (A2) oligomers. I will also assess the effect of altered integrin signaling on A2-mediated changes in dendritic spine and synaptic morphology and glutamate receptor localization. As part of these studies, I will generate mouse models of AD on a background of integrin-linked kinase (Ilk) deletion and assess these mice for plaque formation, synaptic function, network excitability, and behavior. Ilk mediates the functions of most integrin heterodimers implicated in AD, and focusing on this adaptor protein will serve to broadly survey the function of integrins in AD. This work promises to yield important insights into the fundamental biology underlying neurodegeneration and integrin signaling in the adult brain. In addition, this proposal is designed to complement my prior laboratory experiences and provide me with the technical and intellectual tools to become an independent investigator. The Gladstone Institutes and the UCSF Pathology Department are fully committed to making all necessary resources available to facilitate the successful completion of this work. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: There are no disease-modifying therapies for AD, and new approaches to drug discovery are urgently needed. Integrins are a potential new area for AD drug discovery efforts. In particular, the role of integrins in cognitive function suggests that modulating integrin signaling may delay the loss of neuronal connections early in the disease process. My studies promise to reveal the mechanisms by which integrins contribute to AD pathogenesis and to open the way for future drug discovery efforts.