Studies of Hirano Bodies in Living Cells

活细胞中平野体的研究

• 批准号: 7089055
• 负责人: Marcus Fechheimer
• 金额: $ 16.62万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089055
• 关键词: Alzheimer' s disease; amyloid proteins; calcium; cellular pathology; cytoplasm; cytotoxicity; excitatory aminoacid; glutamates; immunocytochemistry; inclusion body; ischemia; laboratory rat; neural degeneration; neurons; oxidative stress; physiologic stressor; transfection /expression vector

DESCRIPTION (provided by applicant): Hirano bodies are cytoplasmic inclusions described in association with the cellular pathology of aging, and a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Since previous studies of Hirano bodies have been performed on preserved clinical brain samples, there is no direct information on the effects of Hirano bodies on cell physiology, aging, or neurodegenerative disease. A model for formation of Hirano bodies in cultured cells has recently been described. The model Hirano bodies are indistinguishable from Hirano bodies in pathology samples in all criteria described by prior ultrastructural and immunohistochemical studies of Hirano bodies. Since Hirano bodies are a widespread type of cytoplasmic protein inclusion associated with numerous significant diseases, it is important to determine their effects on the physiology of neuronal cells. The aim of this project is to test the following 3 alternative hypotheses: 1) Hirano bodies promote/ reflect cellular pathology and toxicity; 2) Hirano bodies are adaptive structures that promote survival of neuronal cells under stresses that are known to contribute to neurodegenerative diseases; or 3) Hirano bodies have no effect on survival of neuronal cells under physiological stress. The effect of Hirano bodies on the neurotoxicity of 5 stresses implicated in the pathology of neurodegenerative disease will be determined. These 5 stresses are: 1) oxidative stress that damages protein, lipid, and nucleic acid; 2) glutamate excitotoxicity that initiates prolonged elevation of intracellular calcium; 3) ischemia (ATP depletion) most commonly associated with stroke or hypoxia; 4) Ab peptide, the leading candidate for initiation of the pathology of Alzheimer's disease; and 5) the intracellular cytoplasmic domain of the amyloid precursor protein (AICD) that can initiate programmed cell death. The results will provide a direct test of the hypothesis that Hirano bodies affect the survival of neuronal cells challenged with physiological stress by promoting either the death or the survival of neurons in disease. Elucidation of the potential roles of Hirano bodies in disease is prerequisite to possible development of animal models, interventions, or therapies.

描述(申请人提供)：平野小体是细胞质内含物，与衰老的细胞病理和各种神经退行性疾病有关，包括阿尔茨海默病、帕金森病和肌萎缩侧索硬化症。由于以前对平野小体的研究是在保存下来的临床脑标本上进行的，因此没有关于平野小体对细胞生理学、衰老或神经退行性疾病的影响的直接信息。最近描述了一个在培养细胞中形成平野小体的模型。在先前对平野小体的超微结构和免疫组织化学研究所描述的所有标准中，模型平野小体与病理标本中的平野小体是无法区分的。由于平野小体是一种广泛存在的细胞质蛋白包涵体，与许多重大疾病有关，因此确定它们对神经细胞生理学的影响是很重要的。该项目的目的是检验以下3个替代假说：1)平野小体促进/反映细胞的病理和毒性；2)平野小体是适应性结构，在已知会导致神经退行性疾病的压力下促进神经细胞的存活；或3)平野小体对生理应激下神经细胞的存活没有影响。将确定平野小体对与神经退行性疾病的病理有关的5种应激的神经毒性的影响。这5种压力是：1)氧化应激，损害蛋白质、脂肪和核酸；2)谷氨酸兴奋毒性，引起细胞内钙长期升高；3)缺血(ATP耗竭)，最常与中风或缺氧有关；4)抗肽，启动阿尔茨海默病病理的主要候选因素；以及5)淀粉样前体蛋白(AICD)的胞内结构域，可启动细胞程序性死亡。这一结果将直接检验这一假设，即平野小体通过促进疾病中神经元的死亡或存活来影响受到生理应激挑战的神经细胞的存活。阐明平野小体在疾病中的潜在作用是可能开发动物模型、干预或治疗的先决条件。