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: 7618395
• 负责人: GRACE Y SUN
• 金额: $ 115.81万
• 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/7618395
• 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）：该计划项目赠款（PPG）的主要目标是探索有助于阿尔茨海默氏病（AD）的新颖且研究不足的途径。 AD患者发现的神经元可塑性和认知记忆丧失降低与慢性氧化应激以及神经毒性寡聚淀粉样蛋白β（A？）的产生增加，导致细胞因子和其他促进神经变性的分子的释放，这些分子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A的慢性作用？生产将对AD患者产生深远的积极影响。基于当前赠款期的有希望的结果，我们建议更好地了解氧化应激和A的影响的机制？在神经元和神经胶质细胞中，会导致预防AD大脑中神经退行性和慢性炎症的信息。我们将使用AD的细胞和动物模型研究神经元，神经胶质和脑微血管中的神经保护和促炎途径。 三个项目将检验以下假设：（1）AD的进展涉及CPLA？/SPLA2/NADPH氧化酶途径的表达和激活，以诱导神经胶质细胞中的炎症反应以及神经元功能的损害； （2）AD中的慢性炎症是由P2Y2受体（P2Y2RS）介导的，用于星形胶质细胞中的细胞因子样核苷酸，通过整合素和生长因子受体的反式激活，P2Y2RS介导神经化的应用程序处理，通过不同的途径介导神经化应用程序，通过不同的途径介导了神经化应用程序，而不是不同的炎症。 （3）他汀类药物既具有由药物诱导的抗凋亡BCL-2转录上调引起的胆固醇独立和依赖性作用机制，它们通过ET-1/Colcinurin/nFAT依赖性途径和抑制Racanylylyylation的抗凋亡BCL-2。两个核心将支持这些项目：（a）管理核心A将监督PPG上的进度； （b）细胞，分子和动物核B将提供原代细胞培养物和转染剂以及转基因小鼠的标准化制剂，制备组织切片并进行免疫组织化学分析，激光捕获微解分解，基因表达的微阵列筛选以及基因表达和分子生物学分析。这些协作研究应确定控制AD中慢性炎症和神经退行性的新型策略。 相关性：痴呆症是一种严重影响一个人进行日常活动的能力的脑部疾病。老年人中最常见的痴呆症形式是阿尔茨海默氏病（AD），最初涉及控制思想，记忆和语言的大脑部分。多达450万美国人无法治愈广告。