ATP-BINDING CASSETTEE TRANSPORTER-2 (ABCA2) REGULATION OF BETA APP PROCESSING

ATP 结合盒转运蛋白 2 (ABCA2) Beta APP 处理的调节

• 批准号: 7959965
• 负责人: WARREN DAVIS
• 金额: $ 14.6万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959965
• 关键词: ATP-Binding Cassette Transporters; Abeta synthesis; Alleles; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Applications Grants; Binding; Brain; Cells; Centers of Research Excellence; Cholesterol; Computer Retrieval of Information on Scientific Projects Database; Esterification; Etiology; Funding; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Homeostasis; Institution; Knockout Mice; Knowledge; LDL-Receptor Related Protein 1; Ligands; Lipoprotein Receptor; Mediating; Microarray Analysis; Molecular Profiling; Mutation; Neuroblastoma; Neurons; Pathway interactions; Peptide Fragments; Presenile Alzheimer Dementia; Prevention; Production; Proteins; Regulation; Reporting; Research; Research Personnel; Resources; Role; Single Nucleotide Polymorphism Map; Source; United States National Institutes of Health; amyloid precursor protein processing; apolipoprotein E-4; base; cholesterol trafficking; genetic risk factor; in vivo; overexpression; protein expression; protein metabolism; therapeutic development

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goals of this project focus on defining mechanisms responsible for processing of the amyloid precursor protein (APP). Amyloidogenic processing of APP results in the generation of Abeta peptide fragments that are involved in the etiology of Alzheimer's disease (AD). The complete elucidation of the mechanisms that regulate APP processing has not been realized. We undertook a screen of ATP-binding cassette transporters expressed in the brain for their effects on APP metabolism. Our current results suggest that the ATP-binding cassette transporter (ABCA2) is a regulator of APP processing and Abeta production. Genetic evidence by single nucleotide polymorphism (SNP) mapping identified a single synonymous mutation in ABCA2 that is significantly associated with early-onset AD. We determined that ABCA2 overexpression in HEK293 cells bearing the APP Swedish mutation (APPsw) increased cellular APP holoprotein levels and Abeta secretion. Using microarray analysis of gene expression profiles in HEK293 cells stably transfected with ABCA2, we detected elevated levels of a number of genes associated with AD. The recent production of an ABCA2 knockout mouse will permit the unequivocal determination of the function of the ABCA2 transporter in regulating APP processing and Abeta production in vivo. A central hypothesis of this grant application is that ABCA2 functions in neuronal cells to regulate APP processing and Abeta production and thereby serves a critical role in maintaining homeostasis between amyloidogenic and non-amyloidogenic pathways of APP metabolism. In depth knowledge of the mechanisms of action of the ABCA2 transporter in vivo on regulation of APP processing will provide a critical basis for the development of therapeutic strategies to reduce Abeta burden in prevention and treatment of AD. This hypothesis will be investigating by pursuing the following the following specific aims: Specific Aim 1. Determine the role of ABCA2 in regulating APP processing and Abeta production in neuronal cells. Since we have previously demonstrated that ABCA2 regulates cellular APP holoprotein levels and Abetasecretion in non-neuronal HEK293 cells, we propose to investigate the specific hypothesis that ABCA2 may regulate APP processing and Abeta production in neuronal cells. Specific Aim 2: Determine the role of ABCA2 in APP processing and Abeta production through ApoE/low-density lipoprotein receptor-related protein (LRP) in neuronal cells. The ApoE4 allele is a strong genetic risk factor for AD and is a ligand for the low-density lipoprotein receptor-related protein, where it mediates esterification of HDL-derived cholesterol. LRP also mediates APP processing and Abeta generation. Since we report that ABCA2 regulates LRP expression in N2a neuroblastoma cells, perhaps by cholesterol trafficking, we propose the specific hypothesis that ABCA2 may regulate APP processing and Abeta generation through ApoE/LRP in neuronal cells.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的长期目标集中于定义负责处理淀粉样蛋白前体蛋白（APP）的机制。 APP的淀粉样生成加工会导致产生与阿尔茨海默氏病（AD）病因相关的Abeta肽片段。尚未实现对调节应用程序处理的机制的完全阐明。 我们为大脑中表达的ATP结合盒转运蛋白的屏幕对APP代谢产生了影响。 我们目前的结果表明，ATP结合盒转运蛋白（ABCA2）是应用程序处理和ABETA生产的调节剂。单核苷酸多态性（SNP）映射的遗传证据确定了ABCA2中的单个同义突变，该突变与早发性AD显着相关。 我们确定带有APP Swedish突变（APPSW）的HEK293细胞中的ABCA2过表达增加了细胞App App多蛋白水平和Abeta分泌。 使用稳定转染ABCA2的HEK293细胞中基因表达谱的微阵列分析，我们检测到与AD相关的许多基因的水平升高。 最近生产的ABCA2基因敲除小鼠将允许明确测定ABCA2转运蛋白在调节体内的应用程序处理和ABETA生产中的功能。 该赠款应用的一个核心假设是，ABCA2在神经元细胞中起作用，以调节应用程序处理和ABETA产生，从而在维持APP代谢的淀粉样蛋白生成和非淀粉样蛋白源性途径之间保持稳态方面起着关键作用。深入了解ABCA2转运蛋白在体内对应用程序处理调节的作用机制将为发展治疗策略的发展提供至关重要的基础，以减轻预防和治疗AD的ABETA负担。 该假设将通过追求以下具体目的来调查： 具体目标1。确定ABCA2在调节神经元细胞中APP加工和ABETA产生中的作用。由于我们以前已经证明ABCA2调节非神经元HEK293细胞中的细胞APP全异蛋白水平和缩质分泌，因此我们建议研究ABCA2可以调节神经元细胞中ABCA2可能调节ABCA2的特定假设。 具体目标2：通过APOE/低密度脂蛋白受体相关蛋白（LRP）在神经元细胞中确定ABCA2在APP加工和ABETA产生中的作用。 APOE4等位基因是AD的强遗传危险因素，是低密度脂蛋白受体相关蛋白的配体，它介导了与HDL衍生的胆固醇的酯化。 LRP还介导应用程序处理和ABETA生成。 由于我们报告了ABCA2调节N2A神经母细胞瘤细胞中LRP的表达，也许是通过胆固醇运输，因此我们提出了以下特定的假设：ABCA2可以通过神经元细胞中的APOE/LRP调节APP加工和ABETA生成。