How does D2-CD33 reduce Alzheimer's disease risk?
D2-CD33 如何降低阿尔茨海默病风险?
基本信息
- 批准号:10038417
- 负责人:
- 金额:$ 42.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAntibodiesBindingBinding ProteinsBrainCell LineCell physiologyCell surfaceCellsClustered Regularly Interspaced Short Palindromic RepeatsDataExonsExtracellular DomainFamilyFinancial compensationGene ExpressionGenesGeneticGenetic PolymorphismITIMImmunoglobulinsImmunosuppressionLectinLengthLigand Binding DomainLinkLocationLogicMediatingMicrogliaModelingMolecular GeneticsNatural ImmunityPTPN6 genePeptidesPhagocytesPhagocytosisPharmacologyPhosphopeptidesPhysiologicalProductionProtein AnalysisProtein IsoformsProteinsProteomicsProxyRNA DecayRegulationReportingRisk FactorsSialic AcidsSignal TransductionSignaling ProteinSingle Nucleotide PolymorphismSmall Interfering RNATerminator CodonTestingTranslatingVariantViralWorkcytokinegain of functiongenetic risk factorgenome wide association studygenomic locushigh riskimmune activationinsertion/deletion mutationloss of functionmembernovelperoxisomeprematureprotective allele
项目摘要
Elucidating the mechanism whereby genetics impact the risk of Alzheimer’s disease (AD) is a
critical barrier to progress in translating genetics to pharmacologic strategies. A polymorphism
near CD33 has been identified as an AD risk factor in multiple genome wide association studies,
including very recent, very large studies. CD33 is a member of the sialic acid-binding
immunoglobulin-type lectin (SIGLEC) family which is linked to regulation of innate immunity.
We and others have found that CD33 expression is restricted to microglia in the brain.
Moreover, the AD-protective allele acts to increase a CD33 isoform lacking exon 2 (D2-CD33) at
the expense of full-length CD33. Since exon 2 encodes the sialic acid ligand binding domain, we
interpreted the finding that loss of exon 2 was associated with decreased AD risk as meaning
that a decrease in functional CD33 and its associated immune suppression was AD-protective.
However, this interpretation needs to be reconsidered given our recent finding that a 4 bp CD33
genetic deletion, which abrogates CD33, is not associated with AD risk. In summary, we
currently propose a model wherein the D2-CD33 isoform represents a gain of function variant to
reduce AD risk because (i) a genetic polymorphism that reduces AD risk increases D2-CD33 at
the expense of “full-length” CD33 but (ii) a CD33 indel that essentially deletes cell surface CD33
does not affect AD risk. To test this model, we propose the following Specific Aims. Specific
Aim 1: Evaluate whether changes in CD33-related gene expression may compensate for CD33
deficiency. Specific Aim 2: Determine D2-CD33 subcellular localization under conditions of
physiologic D2-CD33 expression. Specific Aim 3: Compare CD33 and D2-CD33 interactomes.
Specific Aim 4: Compare impact of CD33 and D2-CD33 on cellular functions critical to
microglia. Successful completion of these studies will pinpoint D2-CD33 as the primary
pharmacologic target in this locus to reduce AD risk.
阐明遗传学影响阿尔茨海默病(AD)风险的机制是
将遗传学转化为药理学策略方面取得进展的关键障碍。A多态
在多基因组范围的关联研究中,NEAR CD33已被确定为AD的危险因素,
包括非常新的、非常大的研究。CD33是唾液酸结合的一员
免疫球蛋白型凝集素(Siglec)家族,与天然免疫调节有关。
我们和其他人发现,CD33的表达仅限于大脑中的小胶质细胞。
此外,AD保护等位基因增加了缺失外显子2的CD33亚型(D2-CD33)。
全长CD33的花费。由于外显子2编码唾液酸配体结合域,我们
将外显子2缺失与AD风险降低相关的发现解释为
功能CD33的减少及其相关的免疫抑制是AD保护作用的结果。
然而,这种解释需要重新考虑,因为我们最近发现,一个4个BP的CD33
取消CD33的基因缺失与AD风险无关。总而言之,我们
目前提出了一个模型,其中D2-CD33异构体代表函数变量T0的增益
降低AD风险是因为(I)降低AD风险的基因多态增加了D2-CD33在
全长CD33的花费,但(Ii)实质上删除细胞表面CD33的CD33插入
不影响AD风险。为了测试该模型,我们提出了以下具体目标。特定的
目的1:评估CD33相关基因表达的变化是否可以补偿CD33
缺乏症。特定目标2:确定D2-CD33的亚细胞定位
生理性D2-CD33的表达。具体目标3:比较CD33和D2-CD33的相互作用。
具体目标4:比较CD33和D2-CD33对细胞功能的影响
小胶质细胞。这些研究的成功完成将确定D2-CD33是主要的
此基因座的药物靶点可降低AD风险。
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)
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Steven Estus其他文献
Steven Estus的其他文献
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{{ truncateString('Steven Estus', 18)}}的其他基金
The surprising impact of APOE alleles on gut microbiome: does altering the microbiome reduce AD risk?
APOE 等位基因对肠道微生物组的惊人影响:改变微生物组是否可以降低 AD 风险?
- 批准号:
9783096 - 财政年份:2018
- 资助金额:
$ 42.08万 - 项目类别:
Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
将 CD33 遗传机制转化为新型阿尔茨海默病治疗方法
- 批准号:
8696452 - 财政年份:2014
- 资助金额:
$ 42.08万 - 项目类别:
Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
将 CD33 遗传机制转化为新型阿尔茨海默病治疗方法
- 批准号:
9251728 - 财政年份:2014
- 资助金额:
$ 42.08万 - 项目类别:
Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
将 CD33 遗传机制转化为新型阿尔茨海默病治疗方法
- 批准号:
9038210 - 财政年份:2014
- 资助金额:
$ 42.08万 - 项目类别:
Urokinase-type plasminogen activator and Alzheimer's
尿激酶型纤溶酶原激活剂与阿尔茨海默病
- 批准号:
6656286 - 财政年份:2002
- 资助金额:
$ 42.08万 - 项目类别:














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