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 阿尔茨海默病（AD）对个体的健康具有破坏性的后果， 社区和社会。AD的根本原因尚未明确阐明。淀粉样蛋白 Aβ42与AD病理学有关，形成淀粉样斑块， 阿尔茨海默病患者的神经元死亡。密集的研究已经确定了α-，β-和γ- 分泌酶作为加工酶，加工淀粉样前体蛋白（APP）以产生 APP、Aβ蛋白和胞内信号结构域的可溶形式。APP如何 加工是由其他蛋白质控制和调节的，以及APP的不同形式如何 蛋白水解产物的功能仍然不清楚。 在这个补充申请中，我们建议识别APP的交互伙伴， APP的突变体和致病形式及其裂解产物，以阐明涉及的途径 在APP的运输和加工中，以及各种蛋白水解产物在APP下的功能 正常和病理状态。我们将利用APEX 2融合蛋白，一种新的方法， 允许非常精确地标记紧密相关的蛋白质以实现该目标。我们将 在小鼠嗅觉系统中进行这组实验。在老年痴呆症中， 功能障碍是病理学的最早表现之一。APP突变体的表达 导致轴突投射模式和突触连接的显著改变。物理 嗅觉感觉神经元及其轴突在不同隔室中的分离使其成为 这是一个容易获得的系统，可以将轴突中的蛋白质功能与细胞体中的蛋白质功能分离。 这项研究将提供急需的在体内检查的途径，处理和相互作用 用APP 这项研究与父母补助金有关。家长补助金的主要目的是了解 发育可塑性的细胞和分子机制，允许精确的神经元 大脑中的连接。在出生后的早期大脑发育过程中， 神经元之间进行精确的功能性连接这种可塑性在成年后下降， 损害神经系统修复损伤和恢复功能的能力。具体 母研究的目标是确定轴突的细胞和分子机制， 在早期发展中确定目标，并确定控制关键时期的机制， 老鼠的嗅觉系统这一补充将把研究扩展到APP的功能， Aβ42，以了解干扰发育可塑性的病理条件。