Role of O-GlcNAcylation in Phosphorylation and Function of Neurofilaments

描述(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，阿尔茨海默病已经成为一个重要的社会、经济和医疗负担，全球约有2700万人受到影响，仅美国就有400-500万人受到影响。由于阿尔茨海默病的分子机制尚不清楚，目前还没有治愈该病的方法。该应用的长期目标是了解阿尔茨海默病神经变性的分子机制，并在此基础上开发预防和治疗该疾病的策略。这项国际研究合作FIRCA奖助金(R03)的具体目标是促进申请者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。由于异常磷酸化(蛋白质被磷酸修饰)和神经丝(神经元的主要细胞骨架蛋白)在大脑中的积累可能导致AD神经元的退化，因此拟议研究的重点是了解O-GlcN酰化(蛋白质被糖修饰)在神经丝的磷酸化和功能中的作用，而神经丝在AD患者的大脑中是异常的。本项目的具体目的是(1)研究O-GlcN酰化对神经细丝组装和轴突运输的功能影响；(2)研究脑内不同区域对O-GlcN酰化降低引起的NF过度磷酸化的易感性。该项目不仅将阐明神经细丝O-GlcN酰化的生物学意义及其功能作用，从而为神经细丝失调在AD神经退行性变中的作用提供基础性的理解，而且还将促进美国和中国之间正在进行的国际研究合作。中国有大约600万阿尔茨海默病患者，对这种疾病的充分研究有着巨大的需求。本次FIRCA申请的外籍合作者是天津医科大学病理生理学副教授邓艳秋博士，天津中国。拟议的研究将在申请人和外国合作者的实验室进行。本申请中建议的研究将补充、扩展和加强申请人的父母资助(NIH R01 AG027429，03/01/06-02/28/11)的意义，该资助旨在研究tau蛋白的O-GlcN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，导致痴呆症和死亡。该项目的目标是加强针对阿尔茨海默病神经退行性变分子机制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.