Soluble TREM2 regulation of microglial function in Alzheimer disease
可溶性 TREM2 对阿尔茨海默病小胶质细胞功能的调节
基本信息
- 批准号:10432584
- 负责人:
- 金额:$ 43.06万
- 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:2022-05-05 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAlzheimer&aposs DiseaseAmericanAmyloid beta-ProteinApoptoticBindingBinding ProteinsBrainCRISPR/Cas technologyCandidate Disease GeneCause of DeathCellsChimeric ProteinsDementiaDepositionDevelopmentDiseaseEngineeringFunctional disorderGeneticHumanImmunologic ReceptorsIntegral Membrane ProteinIntrathecal InjectionsKnockout MiceLipoproteinsMembraneMicrogliaModelingMusPathologyPhagocytosisPhospholipidsPreventionProteinsRegulationRiskRisk FactorsSenile PlaquesSignal TransductionSliceTREM2 geneTYROBP geneTimeUnited StatesVariantbeta amyloid pathologybrain cellcognitive functioncost estimateefficacy evaluationexperimental studygenetic variantgenome wide association studyimprovedmouse modelnovel strategiesnovel therapeuticsprotein aggregationreceptorreceptor bindingtherapy developmenttoolwhole genome
项目摘要
PROJECT SUMMARY
Alzheimer's Disease (AD) is the 6th leading cause of death in the United States and more than 5.8 million
Americans suffer from this disease. This year the estimated cost of AD and other dementias is $305 billion, and
could rise to $1.1 trillion by 2050. The cause of AD remains elusive and is likely multifactorial. The greatest risk
factors are known to be age, genetics, and inheritance. Genome-wide association studies have shown that
variants of TREM2 are associated with two to four times the risk of developing AD. TREM2 is an innate immune
receptor expressed in microglia that has been shown to interact with phospholipids, apoptotic cells, lipoproteins,
and oligomeric forms of amyloid-β (Aβ). This protein has been shown to be required for microglial proliferation,
survival, and phagocytosis of Aβ. TREM2 is a transmembrane protein with no intracellular signaling domains;
signal transduction requires binding to DAP12. Upon microglial activation and clustering, TREM2 is cleaved from
the membrane generating soluble TREM2 (sTREM2). Since both membrane-bound TREM2 and sTREM2
coexist during different stages of AD, it has been difficult to differentiate the extent of which each form
independently contributes to disease pathology. It was recently shown that after intrathecal administration,
sTREM2 binds to microglia, transmitting intracellular signals, promoting survival, improving cognitive function,
and mitigating Aβ pathology; it has been postulated that sTREM2 acts through a putative yet unknown receptor.
In this proposal we will utilize a CRISPR/Cas9 whole genome screen to identify the receptor that binds sTREM2
on microglia and promotes signal transduction. Identified candidate genes will be validated in human microglial
cells and knockout mouse models will be generated to further explore the importance of each in the development
of AD and its pathophysiology. These models will serve as tools that will permit us to identify how sTREM2
modulates microglia independently from membrane-bound TREM2. Such discovery will serve as the basis for
novel therapeutics aimed at modulation of the sTREM2 receptor. sTREM2 has also been shown to bind Aβ
plaques. We will exploit this observation and develop sTREM2-fraction crystallizable(sTREM2-Fc) fusion
proteins that bind Aβ plaques and promote activation of microglia and phagocytosis. The sTREM2-Fc fusion
proteins will be validated using slices of brains from 5XFAD mice that accumulate A plaques typical of AD. We
will also perform intrathecal injections, which will allow us to evaluate the efficacy of sTREM2-Fc in eliminating
plaques and activating microglia. Taken together, these are novel approaches that may help to develop therapies
that enhance clearance and prevention of amyloid-β plaque formation for the treatment of AD.
项目总结
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)
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