Mechanisms by which ABCA7 activity influences Alzheimer's Disease
ABCA7 活性影响阿尔茨海默病的机制
基本信息
- 批准号:10525795
- 负责人:
- 金额:$ 212.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATP binding cassette transporter 1ATP-Binding Cassette TransportersAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmericanApolipoprotein EApolipoproteinsAstrocytesBrainCarrier ProteinsCellsCeramidesCholesterolCodeCognitionDementiaDevelopmentFamily memberFunctional disorderGenetic VariationImpaired cognitionLeadLecithinLipidsMediatingMediator of activation proteinMembraneMemoryMemory LossMicrogliaMusNeuronsOrganPhospholipidsPlasmaPopulationPrevalenceRegulationResearchResearch PersonnelRoleSignal TransductionSpecificityTertiary Protein StructureTestingVariantaging populationbrain cellcell typecognitive functiondaily functioningextracellulargenome wide association studygenomic locusinduced pluripotent stem celllipid metabolismlipid transportlipidomicsmemberneurotransmissionresponsetranslocase
项目摘要
Alzheimer's Disease (AD) is the most common cause of dementia, affecting nearly 6 million Americans and continuing to increase in prevalence with the aging population. AD causes progressive memory loss and cognitive impairment that can eventually lead to the total inability to perform daily functions. The brain is the most cholesterol-rich and lipid-diverse organ in the body and depends on tight regulation of lipid metabolism and transport to maintain proper neural signaling transduction and cognitive function. Several large GWAS have associated the ABCA7 gene locus with AD, with variants that are predicted to have reduced function associated with increased AD risk. ABCA7 is a member of the ATP-binding cassette transporter subfamily A (ABCA), with well described functions as membrane phospholipid (PL) translocases and mediators of cholesterol and lipid efflux from cells. The most characterized ABCA family member is ABCA1, which has been extensively characterized regarding its role in cellular phosphatidylcholine (PC) and cholesterol efflux to extracellular acceptors apolipoproteins apoA1 and apoE. ABCA7 is highly homologous to ABCA1, suggesting that ABCA? mediates transport of certain lipids from inside to outside the cell in response to acceptors like apoA1 and apoE. However, the specific lipids transported by ABCA7 and the mechanisms by which it modulates AD risk have not been established. GWAS of plasma metabolites identified a significant association of the ABCA7 gene locus with certain ceramide species. Lipidomic profiling of Abca7-/- mouse brain revealed dysregulation in several lipid classes, including ceramides, which coincided with impaired cognitive functions, suggesting a functional role of these lipids in memory and cognition. While ABCA1 is also expressed in the brain, the cellular expression of ABCA1 and ABCA 7 is different, and genetic variation at ABCA1 does not carry the same risk of AD at the population level. Therefore, it is hypothesized in this proposal, that ABCA7, in contrast to ABCA1, translocates and promotes cellular efflux of specific lipid species in specific brain cell types in an AD-protective manner, and that reduced ABCA? activity leads to cellular accumulation of toxic lipid species, contributing to neural cell dysfunction and AD. To test this hypothesis, the following research aims are proposed: 1) Determine the specific lipid species affected by deletion of ABCA7 (compared with ABCA1) in three different iPSC-derived brain cells (neurons, microglia, and astrocytes), and establish the effect of ABCA 7 deletion on AD-relevant functions of iPSC derived brain cells; 2) Identify ABCA7 protein domains that differentiate ABCA7 from ABCA1 with regard to specificity of lipid translocase activities; 3) Characterize the functional effects of naturallyoccurring ABCA7 coding variants that are significantly associated with AD.
阿尔茨海默病(AD)是痴呆症的最常见原因,影响近600万美国人,并且随着人口老龄化,患病率继续增加。AD会导致进行性记忆丧失和认知障碍,最终导致完全无法执行日常功能。大脑是体内胆固醇含量最丰富、脂质最多样化的器官,它依赖于对脂质代谢和转运的严格调节来维持适当的神经信号转导和认知功能。几个大的GWAS已经将ABCA 7基因位点与AD相关联,预测其变体具有与AD风险增加相关的功能降低。ABCA 7是ATP结合盒转运子亚家族A(ABCA)的成员,其功能被充分描述为膜磷脂(PL)移位酶和胆固醇和脂质从细胞流出的介质。最具特征的ABCA家族成员是ABCA 1,其在细胞磷脂酰胆碱(PC)和胆固醇流出至细胞外受体载脂蛋白apoA 1和apoE中的作用已被广泛表征。ABCA 7与ABCA 1高度同源,提示ABCA?介导某些脂质从细胞内运输到细胞外,以响应apoA 1和apoE等受体。然而,ABCA 7转运的特定脂质及其调节AD风险的机制尚未确定。血浆代谢物的GWAS确定了ABCA 7基因位点与某些神经酰胺物质的显著相关性。Abca 7-/-小鼠脑的脂质组学分析揭示了包括神经酰胺在内的几种脂质类的调节异常,这与认知功能受损一致,表明这些脂质在记忆和认知中的功能作用。虽然ABCA 1也在大脑中表达,但ABCA 1和ABCA 7的细胞表达是不同的,并且ABCA 1的遗传变异在人群水平上不具有相同的AD风险。因此,它是假设在这一建议,ABCA 7,与ABCA 1,易位和促进细胞流出的特定脂质种类在特定的脑细胞类型中的AD保护的方式,并减少ABCA?活性导致有毒脂质物质的细胞积累,导致神经细胞功能障碍和AD。为了验证这一假设,提出了以下研究目标:1)确定ABCA 7缺失影响的特定脂质种类(与ABCA 1相比)在三种不同的iPSC衍生的脑细胞中(神经元、小胶质细胞和星形胶质细胞)的AD相关功能,并建立ABCA 7缺失对iPSC神经元衍生的脑细胞的AD相关功能的影响; 2)鉴定在脂质移位酶活性的特异性方面区分ABCA 7与ABCA 1的ABCA 7蛋白结构域; 3)表征与AD显著相关的天然存在的ABCA 7编码变体的功能效应。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Daniel James Rader其他文献
Daniel James Rader的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Daniel James Rader', 18)}}的其他基金
Deep Phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 Human Knockouts and Population Based Studies
ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究
- 批准号:
10186801 - 财政年份:2019
- 资助金额:
$ 212.11万 - 项目类别:
Deep phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 human knockouts and population based studies
ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究
- 批准号:
10528964 - 财政年份:2019
- 资助金额:
$ 212.11万 - 项目类别:
UDN@CHOP/UPENN: transition to sustainability
UDN@CHOP/UPENN:向可持续发展过渡
- 批准号:
10905924 - 财政年份:2018
- 资助金额:
$ 212.11万 - 项目类别:
Deep Phenotyping of Human Knockouts and Population Studies of the APOC3 Pathway
人类基因敲除的深度表型分析和 APOC3 通路的群体研究
- 批准号:
9902507 - 财政年份:2017
- 资助金额:
$ 212.11万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulator ApoA-V Using Natural Variants
使用天然变体进行甘油三酯调节剂 ApoA-V 的结构功能分析
- 批准号:
10211481 - 财政年份:2016
- 资助金额:
$ 212.11万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulator ApoA-V Using Natural Variants
使用天然变体进行甘油三酯调节剂 ApoA-V 的结构功能分析
- 批准号:
10605242 - 财政年份:2016
- 资助金额:
$ 212.11万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulators ApoC-III and ApoA-V Using Natural Variants
使用天然变体对甘油三酯调节剂 ApoC-III 和 ApoA-V 进行结构-功能分析
- 批准号:
9306180 - 财政年份:2016
- 资助金额:
$ 212.11万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulators ApoC-III and ApoA-V Using Natural Variants
使用天然变体对甘油三酯调节剂 ApoC-III 和 ApoA-V 进行结构-功能分析
- 批准号:
9158709 - 财政年份:2016
- 资助金额:
$ 212.11万 - 项目类别:
相似海外基金
ATP Binding Cassette Transporters in Health and Disease
健康和疾病中的 ATP 结合盒转运蛋白
- 批准号:
10390366 - 财政年份:2021
- 资助金额:
$ 212.11万 - 项目类别:
ATP Binding Cassette Transporters in Health and Disease
健康和疾病中的 ATP 结合盒转运蛋白
- 批准号:
10237095 - 财政年份:2021
- 资助金额:
$ 212.11万 - 项目类别:
ATP Binding Cassette Transporters in Health and Disease
健康和疾病中的 ATP 结合盒转运蛋白
- 批准号:
10552563 - 财政年份:2021
- 资助金额:
$ 212.11万 - 项目类别:
Photosensitizing Nanoconstructs for Regulation of ATP-Binding Cassette Transporters in the Brain
用于调节大脑中 ATP 结合盒转运蛋白的光敏纳米结构
- 批准号:
2030253 - 财政年份:2020
- 资助金额:
$ 212.11万 - 项目类别:
Standard Grant
Structural and functional studies of iron uptake ATP-binding cassette transporters (ABC transporters) in Gram-negative bacteria
革兰氏阴性菌中铁摄取 ATP 结合盒转运蛋白(ABC 转运蛋白)的结构和功能研究
- 批准号:
20K22561 - 财政年份:2020
- 资助金额:
$ 212.11万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Investigating the mechanism of polysaccharide recognition and export by bacterial ATP-binding cassette transporters
研究细菌 ATP 结合盒转运蛋白识别和输出多糖的机制
- 批准号:
489384-2016 - 财政年份:2018
- 资助金额:
$ 212.11万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Investigating the mechanism of polysaccharide recognition and export by bacterial ATP-binding cassette transporters
研究细菌 ATP 结合盒转运蛋白识别和输出多糖的机制
- 批准号:
489384-2016 - 财政年份:2017
- 资助金额:
$ 212.11万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Investigating the mechanism of polysaccharide recognition and export by bacterial ATP-binding cassette transporters
研究细菌 ATP 结合盒转运蛋白识别和输出多糖的机制
- 批准号:
489384-2016 - 财政年份:2016
- 资助金额:
$ 212.11万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
The Mechanism of ATP Binding Cassette Transporters
ATP 结合盒转运蛋白的机制
- 批准号:
318360 - 财政年份:2014
- 资助金额:
$ 212.11万 - 项目类别:
Fellowship Programs
Heat shock protein 27 attenuates foam cell formation by enhancing cholesterol efflux via the ATP-binding cassette transporters A1
热休克蛋白 27 通过 ATP 结合盒转运蛋白 A1 增强胆固醇流出,从而减弱泡沫细胞形成
- 批准号:
304334 - 财政年份:2014
- 资助金额:
$ 212.11万 - 项目类别: