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: 7610450
• 负责人: WARREN DAVIS
• 金额: $ 17.18万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610450
• 关键词: ATP-Binding Cassette Transporters; Abeta synthesis; Alzheimer' s Disease; Amyloid beta-Protein; Binding; Brain; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Disease; Etiology; Funding; Gene Expression; Generations; Genes; Genetic; Grant; Homeostasis; Institution; Knockout Mice; Learning; Metabolism; Microarray Analysis; Molecular Profiling; Mutation; Neurons; Numbers; Pathway interactions; Peptide Fragments; Performance; Physiological; Process; Production; Protein Overexpression; Proteins; Regulation; Research; Research Personnel; Resources; Role; Single Nucleotide Polymorphism Map; Source; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; amyloid precursor protein processing; early onset; in vivo; mouse model; mutant; neuropathology; research study

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. Amyloidogenic processing of APP results in the generation of Abeta peptide fragments that are involved in the etiology of Alzheimers 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. Although these findings suggest that ABCA2 may be a key regulator of APP metabolism, ABCA2 regulation of APP processing was not examined in either neuronal cells or in transgenic mice expressing mutant forms of APP. 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. We do not know the physiological significance of ABCA2 in regulating APP processing and Abeta production. A central hypothesis of this COBRE project 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. We shall undertake experiments to determine if ABCA2 protein levels modulate APP processing and the consequences for neuropathology and learning performance in transgenic mouse models of the disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 APP 的淀粉样蛋白形成过程会导致 Abeta 肽片段的产生，这些片段参与阿尔茨海默病 (AD) 的病因学。尚未完全阐明调节 APP 处理的机制。 我们对大脑中表达的 ATP 结合盒转运蛋白进行了筛选，以了解它们对 APP 代谢的影响。 我们目前的结果表明 ATP 结合盒转运蛋白 (ABCA2) 是 APP 加工和 Abeta 产生的调节者。通过单核苷酸多态性 (SNP) 作图的遗传证据确定了 ABCA2 中的单个同义突变，该突变与早发性 AD 显着相关。 我们确定携带APP瑞典突变（APPsw）的HEK293细胞中ABCA2过度表达增加了细胞APP全蛋白水平和Abeta分泌。 通过对稳定转染 ABCA2 的 HEK293 细胞中的基因表达谱进行微阵列分析，我们检测到许多与 AD 相关的基因水平升高。 尽管这些发现表明 ABCA2 可能是 APP 代谢的关键调节因子，但在神经元细胞或表达突变形式 APP 的转基因小鼠中并未检测 ABCA2 对 APP 加工的调节。 最近生产的 ABCA2 敲除小鼠将能够明确确定 ABCA2 转运蛋白在体内调节 APP 加工和 Abeta 产生中的功能。 我们不知道 ABCA2 在调节 APP 加工和 Abeta 产生中的生理意义。该 COBRE 项目的一个中心假设是 ABCA2 在神经元细胞中发挥作用，调节 APP 加工和 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生成途径之间的稳态中发挥关键作用。 我们将进行实验以确定 ABCA2 蛋白水平是否调节 APP 处理以及对该疾病的转基因小鼠模型的神经病理学和学习表现的影响。