Mechanisms of Developmental Plasticity in the Mammalian Olfactory System

哺乳动物嗅觉系统发育可塑性机制

• 批准号: 10119618
• 负责人: Congrong Ron Yu
• 金额: $ 30.57万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119618
• 关键词: Address; Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid Proteins; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Axon; Brain; Cells; Chimeric Proteins; Communities; Development; Enzymes; Functional disorder; Goals; Impairment; Individual; Knowledge; Label; Molecular; Mus; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Olfactory Pathways; Parents; Parkinson Disease; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pattern; Personal Satisfaction; Plant Roots; Preventive Intervention; Process; Proteins; Research; Senile Plaques; Signal Transduction; Societies; Synapses; System; alpha secretase; amyloid precursor protein processing; beta secretase; critical period; developmental plasticity; experimental study; functional restoration; gamma secretase; in vivo; mutant; neuron loss; novel strategies; olfactory sensory neurons; parent grant; physical separation; postnatal; protein function; public health relevance; repaired; trafficking

Project Summary Alzheimer’s Disease (AD) has devastating consequences on an individual’s wellbeing, community and society. The root cause of AD has not been clearly elucidated. The amyloid protein Aβ42 has been associated with AD pathology in form amyloid plaques that are thought to cause neuronal death in Alzheimer’s patients. Intensive research has identified the α-, β and γ- secretases as processing enzymes that process the amyloid precursor protein (APP) to produce soluble forms of APP, Aβ proteins and intracellular signaling domains. However, how APP processing is controlled and modulated by other proteins, and how different forms of the APP proteolytic product function, remains unclear. In this supplemental application, we propose to identify the interaction partners of APP, a mutant and pathogenic form of APP, and their cleavage products, to elucidate pathways involved in the trafficking and processing of APP, and the function of various proteolytic products under normal and pathological conditions. We will utilize APEX2 fusion proteins, a novel approach to allow extremely accurate labeling of closely associated protein to achieve this goal. We will conduct this set of experiments in the mouse olfactory system. In Alzheimer’s disease, olfactory dysfunction is one of the earliest manifestations of pathology. Expression of mutant forms of APP causes dramatic alteration of axon projection patterns and synaptic connections. The physical separation of the olfactory sensory neurons and their axons in different compartments make it an easily accessible system to dissociate protein functions in the axons from those in the cell body. This study will provide much needed in vivo examination of pathways that process and interact with APP. This study is relevant to the parent grant. The main goal of the parent grant is to understand the cellular and molecular mechanisms of the development plasticity that permit precise neuronal connections in the brain. During early postnatal brain development, a high level of plasticity allows the neurons to make precise and functional connections. This plasticity declines in the adults, impairing the ability of the nervous system to repair damages and restore function. The specific goals of the parent study are to identify the cellular and molecular mechanisms underlying axon targeting in early development and to identify the mechanism that controls the critical period in the mouse olfactory system. This supplement will extend the study to the function of APP and Aβ42 to understand pathological conditions that interfere with developmental plasticity.

项目摘要 阿尔茨海默氏病（AD）对个人的健康有毁灭性的后果， 社区和社会。 AD的根本原因尚未清楚地阐明。淀粉样蛋白 Aβ42与AD病理学的形式淀粉样菌斑相关，被认为会引起 阿尔茨海默氏症患者的神经元死亡。密集研究已经确定了α-，β和γ- 分泌作为处理淀粉样蛋白前体蛋白（APP）的加工酶 APP，Aβ蛋白和细胞内信号传导域的可溶形式。但是，如何应用 处理由其他蛋白质控制和调节，以及应用程序的不同形式如何 蛋白水解产物功能尚不清楚。 在此补充应用中，我们建议确定应用程序的交互合作伙伴 APP的突变和致病形式及其切割产物，以阐明涉及的途径 在APP的运输和处理中，以及各种蛋白水解产品的功能 正常和病理状况。我们将利用Apex2融合蛋白，这是一种新颖的方法 允许非常准确地标记密切相关的蛋白质以实现此目标。我们将 在小鼠嗅觉系统中进行这组实验。在阿尔茨海默氏病，嗅觉 功能障碍是病理学最早的表现之一。应用程序突变形式的表达 引起轴突投影模式和突触连接的急剧变化。身体 嗅觉感觉神经元及其在不同隔室中的轴突的分离使它成为 易于进入的系统，可以将轴突中的蛋白质功能与细胞体中的蛋白质功能解离。 这项研究将提供对过程和相互作用的途径的急需的体内检查 使用应用。 这项研究与父母赠款有关。父母赠款的主要目标是了解 允许精确神经元的发育塑性的细胞和分子机制 大脑的连接。在产后大脑发育的早期，高水平的可塑性允许 神经元建立精确和功能连接。这种可塑性在成年人中下降， 损害神经系统修复损害和恢复功能的能力。具体 父母研究的目标是确定轴突下的细胞和分子机制 针对早期发展并确定控制关键时期的机制 鼠标嗅觉系统。该补充将将研究扩展到应用程序的功能和 Aβ42了解干扰发育可塑性的病理状况。