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。 APP的淀粉样生成加工导致与阿尔茨海默氏病（AD）病因相关的Abeta肽片段产生。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。 尽管这些发现表明ABCA2可能是APP代谢的关键调节剂，但在神经元细胞或表达APP突变形式的转基因小鼠中，ABCA2调节ABCA2的调节均未检查。 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。 我们不知道ABCA2在调节应用程序处理和ABETA生产中的生理意义。这个毛刺项目的一个核心假设是，ABCA2在神经元细胞中的作用来调节APP加工和ABETA生产，从而在维持APP代谢的淀粉样蛋白生成和非淀粉样酶途径之间保持稳态方面起着至关重要的作用。 我们将进行实验，以确定ABCA2蛋白水平是否调节应用程序处理以及对疾病转基因小鼠模型中神经病理学和学习性能的后果。