Sex-Specific Single Cell Expression Profiles, Genetic Risk and Drug Responsiveness in Alzheimer's Disease
阿尔茨海默病的性别特异性单细胞表达谱、遗传风险和药物反应
基本信息
- 批准号:10467589
- 负责人:
- 金额:$ 125.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAllelesAlzheimer disease preventionAlzheimer&aposs DiseaseAlzheimer&aposs Disease PathwayAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer&aposs disease therapeuticAmyloid beta-ProteinArchitectureAutopsyBiologicalBrainBrain regionCell NucleusCellsClinical TrialsCoupledDataData CollectionDependenceDevelopmentDiseaseDisease susceptibilityEnrollmentFemaleGene ExpressionGene Expression ProfileGenesGeneticGenetic ModelsGenetic RiskGenetic TranscriptionGoalsHeterogeneityHistologicHumanHuman GeneticsImmuneImpaired cognitionInflammatoryKnock-inKnock-in MouseKnowledgeLate Onset Alzheimer DiseaseLearningMERTK geneMemoryMicrogliaMolecularMorphologyMusMutationNerve DegenerationNeurobehavioral ManifestationsNeurodegenerative DisordersNeuronsOnset of illnessOutcomePathway interactionsPatternPerformancePharmaceutical PreparationsPhenotypePre-Clinical ModelPrevention therapyReceptor Protein-Tyrosine KinasesRecoveryReportingResolutionRiskRoleSeveritiesSex DifferencesSmall Nuclear RNAStructure of middle temporal gyrusSynapsesTestingTherapeuticTherapeutic InterventionTreatment EffectivenessVariantWomanagedbrain cellbrain tissuecell typecohortdisease phenotypedrug developmenteffective interventioneffective therapyexperimental studygain of functiongenetic variantgenome wide association studygenome-widegenome-wide analysishigh riskhuman datainsightmalemenmouse modelneuroinflammationnovelpreservationresponserisk variantsextau aggregationtooltranscriptome sequencingtranscriptomicstreatment response
项目摘要
PROJECT SUMMARY
Alzheimer’s disease (AD) is characterized by progressive cognitive decline coupled with accumulation of brain
amyloid-ß and tau aggregates. Despite being the most common neurodegenerative disease, there is no effective
treatment available to slow or halt the fatal progression of AD. Two thirds of AD patients are females, and women
have a higher risk of developing AD. Women with AD have more extensive brain histological changes than men
with AD, more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease
affects female and male brains differentially. Despite evident AD sex variance, the mechanisms and pathways
are still poorly understood. Thus, a focus on sex differences in AD is essential to move the field towards effective
interventions and to develop sex-specific therapies.
We hypothesize that female and male brains present critically distinct disease susceptibilities and responses to
AD pathology, specifically with regard to immune architecture and CNS synapse plasticity. Our Preliminary single
nucleus RNA sequencing (snRNA-seq) profiles of post-mortem human AD brains revealed sex-specific
differences in cellular composition and neuroinflammatory features. We identified marker gene sets for AD-
associated female-specific microglia subpopulations and assessed these gene sets through re-analysis of
genome wide association study (GWAS) data. The proposed additional human data collection and statistical
assessments will delineate the molecular architecture of the diverse brain cell responses affected by AD and
sex, and is expected to identify multiple sex-specific candidate AD risk genes. The Preliminary studies have
already revealed known female-biased and novel female-specific AD risk genes, such as APOE and MERTK.
We will define the sex-specific role of MERTK in the determination of AD risk and neuroinflammation using
conditional mouse MERTK alleles and AD knock-in mice. In mouse models, we will define at single cell resolution
the extent to which sex-specific expression responses to knock-in of FAD mutations overlap with human Late
Onset AD sex-specific expression patterns, as well as sex-dependent differences in gene expression profiles
responding to treatment with a synapse-preserving therapeutic. The results from our study will identify sex-
specific genes and pathways for AD onset, progression, and treatment response, offering new biological insights
for AD prevention and therapy.
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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Sourav Ghosh其他文献
Sourav Ghosh的其他文献
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{{ truncateString('Sourav Ghosh', 18)}}的其他基金
Augmenting AXL and MERTK function to restrain cognitive decline and improve health span in mouse models of Alzheimer's Disease
增强 AXL 和 MERTK 功能以抑制阿尔茨海默氏病小鼠模型的认知衰退并改善健康寿命
- 批准号:
10662677 - 财政年份:2023
- 资助金额:
$ 125.57万 - 项目类别:
Naïve T cell archetypes and anti-tumor immunity
幼稚 T 细胞原型和抗肿瘤免疫
- 批准号:
10741153 - 财政年份:2023
- 资助金额:
$ 125.57万 - 项目类别:
An innate immune checkpoint in cancer immunotherapy
癌症免疫治疗中的先天免疫检查点
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9447148 - 财政年份:2017
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$ 125.57万 - 项目类别:
An innate immune checkpoint in cancer immunotherapy
癌症免疫治疗中的先天免疫检查点
- 批准号:
10286793 - 财政年份:2017
- 资助金额:
$ 125.57万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8657870 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8461275 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶底极性信号传导
- 批准号:
8817344 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶底极性信号传导
- 批准号:
8915298 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8649817 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
Apical-basal polarity signaling in glioblastoma
胶质母细胞瘤中的顶端-基底极性信号传导
- 批准号:
8527897 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
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