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.

项目概要 阿尔茨海默病 (AD) 对个人的健康造成毁灭性后果， 社区和社会尚未明确阐明AD的根本原因。 Aβ42 与 AD 病理学相关，其形式为淀粉样斑块，被认为是导致 深入的研究已经确定了阿尔茨海默病患者的神经死亡。 分泌酶作为加工酶，加工淀粉样前体蛋白（APP）以产生 APP、Aβ 蛋白和细胞内信号传导结构域的可溶形式 然而，APP 的作用如何。 加工过程是由其他蛋白质控制和调节的，以及不同形式的 APP 如何控制和调节 蛋白水解产物的功能尚不清楚。 在此补充申请中，我们建议确定 APP 的交互合作伙伴， APP 的突变体和致病形式及其裂解产物，以阐明相关途径 在APP的贩运和加工中，以及各种蛋白水解产品的功能 我们将利用 APEX2 融合蛋白，这是一种新的方法来检测正常和病理条件。 允许极其准确地标记密切相关的蛋白质以实现这一目标。 在小鼠嗅觉系统中进行这组实验，研究阿尔茨海默病的嗅觉。 功能障碍是 APP 突变形式表达的最早的病理表现之一。 导致轴突投射模式和突触连接的巨大改变。 嗅觉感觉神经元及其轴突分离在不同的隔间中，使其成为 易于使用的系统，可将轴突中的蛋白质功能与细胞体中的蛋白质功能分离。 这项研究将为处理和相互作用的途径提供急需的体内检查 与应用程序。 这项研究与家长补助金相关。家长补助金的主要目标是了解。 发育可塑性的细胞和分子机制，允许精确的神经 在出生后早期大脑发育过程中，大脑中的连接具有高水平的可塑性。 神经元建立精确和功能性连接的可塑性在成年人中下降， 损害神经系统修复损伤和恢复功能的能力。 父研究的目标是确定轴突背后的细胞和分子机制 确定早期发展的目标并确定控制关键期的机制 小鼠嗅觉系统的补充将研究扩展到APP和功能。 Aβ42 用于了解干扰发育可塑性的病理状况。