Cell models for AD:Lipids and related signaling pathways

描述：老年痴呆症？阿尔茨海默病（AD）是最昂贵和最具破坏性的疾病， 21世纪的神经退行性疾病为了征服AD，治疗必须 以预防疾病的神经病理学表现。 广泛认为AD脑内β淀粉样蛋白（AB）斑块的积聚 引起氧化损伤和炎症反应， 激活，这反过来又导致神经元细胞死亡。很多因素， 包括载脂蛋白、磷脂和胆固醇， AB的聚集及其细胞毒作用。有证据表明 细胞膜脂质和G蛋白偶联受体功能的变化 AB在AD脑中的细胞毒性作用。该计划的主要地点 项目资助（PPG）是1）检查AB和氧化应激的影响 与AD表型相关的神经细胞功能，包括激活 磷脂酶、环加氧酶和G蛋白偶联受体，和2） 确定胆固醇稳态，脂蛋白和AD之间的关系。 这个高度集成的PPG，由Grace Sun博士指导，由一个 行政核心，细胞培养核心和三个研究项目。项目 #1（G. Sun，PL）将确定AB和脂蛋白对氧化应激的影响。 以及磷脂酶A2介导的神经细胞炎症反应。 项目2（G. Weisman，PL）将确定AB和脂蛋白的作用 G蛋白偶联P2Y2核苷酸受体在神经胶质细胞和神经元中的功能 细胞项目#3（G. Wood，PL）将确定AB如何影响胆固醇 在细胞膜和亚细胞内的稳态、运输和分布 细胞器通过了解脂质、脂蛋白和受体介导的 AD病理学中的细胞信号通路，拟议的研究将 提供重要的新信息，将影响发展 有效的药物治疗方法。

DESCRIPTION: Alzheimer?s disease (AD) is the most costly and devastating neurodegenerative disorder of the 21st century. To conquer AD, therapies must be developed to prevent the neuropathological manifestations of the disease. It is widely held that accumulation of beta amyloid (AB) plaques in AD brain causes oxidative damage and inflammatory responses involving glial cell activation that, in turn, leads to neuronal cell death. Many factors, including apolipoproteins, phospholipids and cholesterol, can influence aggregation of AB and its cytotoxic actions. There is evidence for the roles of plasma membrane lipids and G protein-coupled receptor functions in the cytotoxic effects of AB in the AD brain. The major loci of this Program Project Grant (PPG) are 1) to examine the effects of AB and oxidant stressors on neural cell functions relevant to the AD phenotype, including activation of phospholipases, cyclo-oxygenases and G protein-coupled receptors, and 2) to determine relationships between cholesterol homeostasis, lipoproteins and AD. This highly integrated PPG, directed by Dr. Grace Sun, consists of an Administrative Core, a Cell Culture Core and three research projects. Project #1 (G. Sun, PL) will determine the effects of AB and lipoproteins on oxidative and inflammatory responses in neural cells mediated by phospholipases A2. Project #2 (G. Weisman, PL) will determine the effects of AB and lipoproteins on G protein-coupled P2Y2 nucleotide receptor functions in glial and neuronal cells. Project #3 (G. Wood, PL) will determine how AB affects cholesterol homeostasis, transport and distribution in cell membranes and subcellular organelles. By understanding the role of lipids, lipoproteins, and receptor-mediated cell signaling pathways in AD pathology, the proposed studies will provide important new information that will impact the development of effective pharmacotherapies for this debilitating disease.