Therapeutic potential of GMF suppresssion in inflammation and neurodegeneration

GMF 抑制在炎症和神经退行性疾病中的治疗潜力

基本信息

批准号：
9137608
负责人：
ASGAR ZAHEER
金额：
$ 31.47万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137608
关键词：
Affect Age Alzheimer&apos s Disease American Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Antibodies Astrocytes Behavioral Biological Factors Brain region Chromosomes, Human, Pair 14 Chronic Clinical Cognition Cognitive Data Dementia Developed Countries Development Diagnosis Disease Effectiveness Elderly Environmental Risk Factor Etiology Event Functional disorder Gender Genes Genetic Glia Maturation Factor Goals Health Impairment In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-6 Knockout Mice Laboratories Lead Link MAP Kinase Gene MAPK14 gene Mediating Mediator of activation protein Memory Memory Loss Microglia Molecular Morbidity - disease rate Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Nuclear Oligodendroglia Oxidative Stress Pathogenesis Pathology Pathway interactions Phenotype Phosphotransferases Prevalence Prevention Process Production Proteins RNA Interference Research Risk Factors Role Senile Plaques Signal Transduction Site Stimulus Stress Symptoms TNF gene Tauopathies Testing Therapeutic Therapeutic Agents Therapeutic Intervention Treatment Efficacy Work age related apolipoprotein E-2 base brain cell brain tissue cognitive change cytokine density effective therapy glial activation human genome sequencing human old age (65+)hyperphosphorylated tau in vivo inhibitor/antagonist mortality mouse model nerve supply neurochemistry neuron loss neuropsychiatry neurotoxic neutralizing antibody non-demented novel novel therapeutic intervention presenilin-1 small hairpin RNA success targeted treatment tau dysfunction tau mutation transcription factor

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia among elderly, affecting 5 million Americans and over 25 million individuals worldwide. AD is an age-related neurodegenerative disease, with approximately 7% of people older than 65 years and about 40% of people older than 80 years being affected in industrialized countries. AD is characterized by the accumulation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) leading to eventual neuronal death. Studies have shown that NFTs, a defining feature correlated well with the clinical expression of dementia in AD. The role of astrocytes and microglia in mounting an inflammatory response could contribute to the pathogenesis of the disease. Such inflammatory response involves the production of cytokines that are intricately linked to the oxidative stress and stress-activated signal transduction events. The symptoms of AD are characterized by loss of memory, progressive impairment of cognition, and various behavioral and neuropsychiatric disturbances. The etiology of AD remains unknown, but the risk factors include genetic, biological and environmental factors. However, there is no definite treatment yet available for AD. Current proposal builds on our previous work that has provided support for our hypothesis that glia maturation factor (GMF) is involved in neuronal degeneration associated with neurodegenerative diseases, especially AD. We propose to investigate the hypothesis that intracellular GMF is associated with the pathophysiology of AD, as well as investigating the effectiveness of suppression of endogenous GMF-function as an effective and selective strategy to slow, and perhaps reverse, pathogenic processes. Two Specific Aims will be pursued. In Aim 1, we will test the hypothesis that the progressive AD pathogenesis is associated with the enhanced GMF expression and GMF is preferentially localized to sites of amyloid plaques and neurofibrillary tangles in AD affected brain regions. We will examine brain tissues from clinically diagnosed and neuropathologically confirmed AD cases and age- and gender-matched non-demented controls. We will quantitatively evaluate the regional densities of APs, NFTs, reactive glia (neuroprotective and neurotoxic phenotypes), and determine relationship to the prevalence, distribution and concentration of GMF in AD and age-matched non-demented controls. In Aim 2, we will evaluate the effects of suppression of GMF-functions with (A) GMF-specific shRNA, and (B) GMF-specific antibody in two animal models of AD-relevant pathophysiology: (1) 5XFAD mouse expressing 5 different mutations (3 in APP and 2 in presenilin-1), and (2) rTg4510 mouse model of tauopathy. We will evaluate the GMF-function suppression strategy in the context of inflammation and neurodegeneration; compare the histopathological features, neurochemical changes, and cognitive memory functions. The present study has significant clinical implications, and provides an efficient in vivo approach to test GMF-inhibitors as therapeutic agents for neurodegenerative diseases.

描述（由适用提供）：阿尔茨海默氏病（AD）是老年痴呆症的最常见形式，影响了500万美国人，全球超过2500万个人。 AD是一种与年龄相关的神经退行性疾病，大约7％的65岁以上的人和约40％的80岁以上的人在工业化国家受到影响。 AD的特征是淀粉样pla斑（AP）和神经原纤维缠结（NFTS）的积累导致最终神经元死亡。研究表明，NFTS（一个定义特征）与AD中痴呆症的临床表达良好相关。星形胶质细胞和小胶质细胞在炎症反应中的作用可能有助于疾病的发病机理。这种炎症反应涉及与氧化应激和应激激活信号转导事件相关的细胞因子的产生。 AD的症状的特征是记忆力丧失，认知的进行性损害以及各种行为和神经精神疾病。 AD的病因仍然未知，但风险因素包括遗传，生物学和环境因素。但是，尚无定义的AD治疗。当前的提案基于我们以前的工作，这为我们的假设提供了支持，即神经胶质成熟因子（GMF）参与与神经退行性疾病相关的神经元变性，尤其是AD。我们提出了以下假设：细胞内GMF与AD的病理生理学有关，并研究了抑制内源性GMF功能的有效性，这是一种有效且有选择性的策略，以减慢且可能逆转病原体过程。将追求两个具体的目标。在AIM 1中，我们将检验以下假设：渐进的AD发病机理与GMF的增强和GMF相关，而GMF优先定位于AD受影响的大脑区域中淀粉样蛋白斑块和神经纤维缠结的位点。我们将检查临床诊断和神经病理学确认的AD病例以及年龄和性别匹配的非痴呆对照的脑组织。我们将定量评估AP，NFT，反应性神经胶质（神经保护性和神经毒性表型）的区域密度，并确定与AD中GMF的患病率，分布和浓度的关系以及年龄匹配的非抑制作用。在AIM 2中，我们将评估（a）GMF特异性shRNA抑制GMF功能的效果，以及（b）GMF特异性抗体在两个相关的病理生理学的动物模型中：（1）5XFAD表达5个不同突变的5XFAD小鼠（在App中为App中的3个和2个在Presenilin-1中的2），以及2）和（2）RTG4510小鼠模型。我们将在感染和神经变性的背景下评估GMF功能抑制策略；比较组织病理学特征，神经化学变化和认知记忆功能。本研究具有显着的临床意义，并提供了一种有效的体内方法来测试GMF抑制剂作为神经退行性疾病的治疗剂。