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（由申请人提供）：阿尔茨海默病 (AD) 是老年人中最常见的痴呆症，影响着 500 万美国人，全世界有超过 2500 万人 AD 是一种与年龄相关的神经退行性疾病，大约 7% 的人年龄超过 10 岁。在工业化国家，65 岁以上的老年人和约 40% 的 80 岁以上老年人受到 AD 的影响，其特点是淀粉样斑块 (AP) 和神经原纤维缠结的积累。研究表明，NFT 与 AD 痴呆的临床表现密切相关，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该疾病的发病机制。反应涉及与氧化应激和应激激活信号转导事件密切相关的细胞因子的产生。AD 的症状特征是记忆丧失、认知进行性损害以及各种行为和神经精神症状。 AD 的病因仍不清楚，但其危险因素包括遗传、生物和环境因素。然而，目前的建议是建立在我们之前的研究基础上的，该研究为我们的神经胶质成熟假设提供了支持。因子（GMF）参与与神经退行性疾病，特别是 AD 相关的神经元变性，我们建议研究细胞内 GMF 与 AD 病理生理学相关的假设，并研究抑制内源性 GMF 功能作为有效方法的有效性。我们将追求减缓甚至逆转致病过程的选择性策略。在目标 1 中，我们将检验以下假设：渐进性 AD 发病机制与 GMF 表达增强有关，并且 GMF 优先定位于淀粉样蛋白位点。我们将检查临床诊断和神经病理学证实的 AD 病例以及年龄和性别匹配的非痴呆对照的脑组织。在目标 2 中，我们将评估 AP、NFT、反应性神经胶质细胞（神经保护和神经毒性表型）的区域密度，并确定与 AD 和年龄匹配的非痴呆对照中 GMF 的患病率、分布和浓度的关系。在 AD 相关病理生理学的两种动物模型中，使用 (A) GMF 特异性 shRNA 和 (B) GMF 特异性抗体抑制 GMF 功能：(1) 5XFAD表达 5 种不同突变的小鼠（3 个在 APP 中，2 个在 presenilin-1 中），以及 (2) rTg4510 tau 蛋白病小鼠模型，我们将在炎症和神经退行性变的背景下评估 GMF 功能抑制策略；本研究具有重要的临床意义，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。