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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 APP的淀粉样加工导致产生与阿尔茨海默病病因学有关的Abeta肽片段的疾病（AD）。调节APP加工的机制尚未完全阐明。 我们进行了一个屏幕的ATP结合盒转运蛋白表达在大脑中的APP代谢的影响。 我们目前的研究结果表明，ATP结合盒转运蛋白（ABCA 2）是APP加工和Abeta生产的调节剂。通过单核苷酸多态性（SNP）作图的遗传证据确定了ABCA 2中与早发性AD显著相关的单个同义突变。 我们确定ABCA 2在携带APP瑞典突变（APPsw）的HEK 293细胞中的过表达增加了细胞APP全蛋白水平和Abeta分泌。 使用基因表达谱的微阵列分析稳定转染ABCA 2的HEK 293细胞，我们检测到一些与AD相关的基因水平升高。 虽然这些研究结果表明，ABCA 2可能是一个关键的调节APP代谢，ABCA 2调节APP加工没有检查在神经元细胞或在转基因小鼠表达突变形式的APP。最近生产的ABCA 2基因敲除小鼠将允许明确确定的ABCA 2转运蛋白的功能，在调节APP加工和体内Abeta生产。 我们不知道ABCA 2在调节APP加工和Abeta产生中的生理意义。该COBRE项目的中心假设是ABCA 2在神经元细胞中起调节APP加工和Abeta产生的作用，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起关键作用。 我们将进行实验，以确定ABCA 2蛋白水平是否调节APP加工和神经病理学的后果和疾病的转基因小鼠模型的学习表现。