Cell Models for AD: Lipids and Related Signaling Pathways

AD 细胞模型：脂质和相关信号通路

• 批准号: 7410043
• 负责人: GRACE Y SUN
• 金额: $ 112.44万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410043
• 关键词: Cell; Models; AD; Lipids; Related

DESCRIPTION (provided by applicant): The major goal of this Program Project Grant (PPG) is to explore novel and under-studied pathways that contribute to Alzheimer's disease (AD). The decreased neuronal plasticity and cognitive memory loss found in people with AD is associated with chronic oxidative stress and increased production of neurotoxic oligomeric amyloid beta (A?) that cause release of cytokines and other molecules that promote neurodegeneration and chronic inflammation. We believe that devising methods to limit chronic effects of oxidative stress and oligomeric A? production would have profoundly positive consequences for AD patients. Based on promising results in the current grant period, we propose to better understand the mechanisms underlying the effects of oxidative stress and A? in neurons and glial cells, information that will lead to better treatments for prevention of neurodegeneration and chronic inflammation in the AD brain. We will investigate neuroprotective and pro-inflammatory pathways in neurons, glia and brain microvessels using cell and animal models of AD. Three projects will test the hypotheses that: (1) progression of AD involves expression and activation of the cPLA?/sPLA2/NADPH oxidase pathways to induce inflammatory responses in glial cells and impairment of neuronal functions; (2) chronic inflammation in AD is mediated by P2Y2 receptors (P2Y2Rs) for cytokine-like nucleotides in astrocytes and cerebral microvessels through transactivation of integrins and growth factor receptors, and P2Y2Rs mediate neuroprotective APP processing by a different pathway than inflammation; and (3) statins have both cholesterol-independent and -dependent mechanisms of action that are neuroprotective due to drug-induced transcriptional up-regulation of anti-apoptotic Bcl-2 by ET- 1/calcinurin/NFAT-dependent pathways and inhibition of Rac1 geranylgeranylation. Two cores will support the projects: (A) Administrative Core A will oversee progress on the PPG; (B) Cell, Molecular, and Animal Core B will provide standardized preparations of primary cell cultures and transfectants, and transgenic mice, prepare tissue sections, and perform immunohistochemical analyses, Laser Capture Microdissection, microarray screening of gene expression, and molecular biology assays. These collaborative studies should identify novel strategies to control chronic inflammation and neurodegeneration in AD. RELEVANCE: Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities. The most common form of dementia among older people is Alzheimer's disease (AD), which initially involves the parts of the brain that control thought, memory, and language. Up to 4.5 million Americans suffer from AD from which there is no cure.

描述（由申请人提供）：本项目拨款（PPG）的主要目标是探索导致阿尔茨海默病（AD）的新颖和未被研究的途径。阿尔茨海默氏症患者的神经元可塑性下降和认知记忆丧失与慢性氧化应激和神经毒性低聚淀粉样蛋白（A?）的产生增加有关，后者会导致细胞因子和其他分子的释放，从而促进神经变性和慢性炎症。我们认为，设计方法来限制氧化应激和低聚物A？会对AD患者产生深远的积极影响。基于当前资助期的有希望的结果，我们建议更好地了解氧化应激和A？在神经元和神经胶质细胞中，这些信息将导致更好的治疗方法，以预防阿尔茨海默病大脑中的神经变性和慢性炎症。我们将利用AD的细胞和动物模型研究神经元、胶质细胞和脑微血管中的神经保护和促炎通路。