Role of O-GlcNAcylation in Phosphorylation and Function of Neurofilaments

描述（由申请人提供）：阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病。由于全球老年人口规模的增加，AD已成为重要的社会、经济和医疗负担，影响全球约2700万人，仅在美国就有4-5百万人。由于AD的分子机制尚不清楚，迄今为止还没有治愈该病的方法。本申请的长期目标是了解AD中神经变性的分子机制，并在此基础上制定预防和治疗该疾病的策略。FIRCA国际研究合作基金（R 03）的具体目标是促进申请人在美国的实验室与外国合作者在中国的实验室之间的国际研究合作。因为异常的磷酸化（磷酸盐对蛋白质的修饰）和神经丝的积累脑中的O-GlcNAc（神经元的主要细胞骨架蛋白）可能导致AD中神经元的变性，所提议的研究的具体重点是理解O-GlcNAc酰化的作用。（糖对蛋白质的修饰）在神经丝的磷酸化和功能中的作用，这在AD患者的大脑中是异常的。本项目的具体目的是（1）研究O-GlcNAc化对神经丝组装和轴突运输的功能影响，以及（2）研究脑中O-GlcNAc化降低诱导的不同脑区对NF过度磷酸化的脆弱性。该项目不仅将阐明神经丝O-GlcNAc酰化的生物学相关性及其功能作用，从而为神经丝失调在AD神经变性中的作用提供基础性认识，而且还将促进中美之间正在进行的国际研究合作。中国约有600万人患有AD，对该疾病的充分研究有巨大的需求。该FIRCA申请的外国合作者是中国天津医科大学病理生理学副教授Yanqiu Deng博士。拟议的研究将在申请人和外国合作者的实验室进行。本申请中提出的研究将补充、扩展和增强申请人的母基金（NIH R 01 AG 027429，03/01/06-02/28/11）的重要性，该母基金的目标是tau蛋白的O-GlcNAc酰化参与AD神经变性的机制。公共卫生相关性：阿尔茨海默病是一种与年龄相关的进行性神经退行性疾病，其特征是记忆、思维和行为受损，导致痴呆和死亡。该项目的目的是加强针对阿尔茨海默病神经变性分子机制的研究的国际研究合作，并在此基础上制定预防和治疗该疾病的策略。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is an age-related progressive neurodegenerative disease. As a result of increases in the size of the aged population worldwide, AD has become an important social, economical and medical burden, affecting ~27 million individuals worldwide and 4-5 million individuals in the U.S. alone. Because the molecular mechanism of AD is not yet understood, there is no cure for the disease so far. The long-term objective of this application is to understand the molecular mechanism of the neurodegeneration in AD and, based on this knowledge, to develop strategies to prevent and treat the disease. The specific goal of this international research collaboration FIRCA grant (R03) is to foster international research collaboration between the applicant's laboratory in the U.S. and the foreign collaborator's laboratory in China. Because abnormal phosphorylation (a modification of protein by phosphate) and accumulation of neurofilaments (the major cytoskeletal proteins of the neuron) in the brain may contribute to degeneration of neurons in AD, the specific focus of the proposed studies is on understanding the role of O-GlcNAcylation (a modification of protein by sugar) in the phosphorylation and function of neurofilaments, which are abnormal in the brains of individuals with AD. The Specific Aims of this project are to (1) study the functional impact of O-GlcNAcylation on filament assembly and on axonal transport of neurofilaments and (2) study the vulnerability of various brain regions to NF hyperphosphorylation induced by decreased O-GlcNAcylation in the brain. This project will not only elucidate the biological relevance of neurofilament O-GlcNAcylation and its functional roles, thus providing the fundamental understanding of the role of dysregulation of neurofilaments in neurodegeneration of AD, but also foster the ongoing international research collaboration between the U.S. and China. With ~6 million individuals with AD, China has a huge demand for adequate research on the disease. The foreign collaborator of this FIRCA application is Dr. Yanqiu Deng, an Associate Professor of Pathophysiology at Tianjin Medical University, Tianjin, China. The proposed studies will be carried out at both the applicant's and the foreign collaborator's laboratories. Studies proposed in this application will complement, extend and enhance the significance of the applicant's parent grant (NIH R01 AG027429, 03/01/06-02/28/11) that targets the mechanism of the involvement of O-GlcNAcylation of tau protein in the neurodegeneration of AD. PUBLIC HEALTH RELEVANCE: Alzheimer disease is an age-related progressive neurodegenerative disease and is characterized by impaired memory, thinking, and behavior, leading to dementia and death. The objective of this project is to enhance international research collaboration on studies targeting the molecular mechanism of neurodegeneration of Alzheimer disease and, on the basis of this knowledge, to develop strategies to prevent and treat the disease.