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.
项目摘要
阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性认知功能减退为特征的疾病,
淀粉样蛋白-β和tau聚集体。尽管是最常见的神经退行性疾病,
可用于减缓或停止AD致命性进展的治疗。三分之二的AD患者是女性,
患AD的风险更高。女性AD患者比男性有更广泛的脑组织学改变
与AD,更严重的认知症状,更严重的神经退行性变,这表明,疾病,
对女性和男性大脑的影响不同尽管AD存在明显的性别差异,
仍然知之甚少。因此,关注AD中的性别差异对于将该领域推向有效
干预措施和开发针对性别的治疗方法。
我们假设,女性和男性的大脑呈现出严重不同的疾病易感性和反应,
AD病理学,特别是关于免疫结构和CNS突触可塑性。我们的初步单
尸检人类AD大脑的核RNA测序(snRNA-seq)图谱显示性别特异性
细胞组成和神经炎症特征的差异。我们确定了AD的标记基因组-
相关的女性特异性小胶质细胞亚群,并通过重新分析这些基因集,
全基因组关联研究(GWAS)数据。拟议的额外人类数据收集和统计
评估将描绘受AD影响的不同脑细胞反应的分子结构,
性别,并有望确定多个性别特异性候选AD风险基因。初步研究表明,
已经揭示了已知的女性偏见和新的女性特异性AD风险基因,如APOE和MERTK。
我们将使用以下方法确定MERTK在确定AD风险和神经炎症中的性别特异性作用:
条件性小鼠MERTK等位基因和AD敲入小鼠。在小鼠模型中,我们将以单细胞分辨率定义
对FAD突变敲入的性别特异性表达应答与人类晚期
发病AD性别特异性表达模式,以及基因表达谱的性别依赖性差异
对突触保护治疗有反应我们的研究结果将确定性别-
AD发病、进展和治疗反应的特定基因和途径,提供新的生物学见解
用于AD预防和治疗。
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 }}
Sourav Ghosh其他文献
Sourav Ghosh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('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
- 批准号:
9447148 - 财政年份:2017
- 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
- 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:
8527897 - 财政年份:2010
- 资助金额:
$ 125.57万 - 项目类别:
相似海外基金
Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
- 批准号:
502556 - 财政年份:2024
- 资助金额:
$ 125.57万 - 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
- 批准号:
10659303 - 财政年份:2023
- 资助金额:
$ 125.57万 - 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
- 批准号:
10674405 - 财政年份:2023
- 资助金额:
$ 125.57万 - 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
- 批准号:
10758772 - 财政年份:2023
- 资助金额:
$ 125.57万 - 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
- 批准号:
10676499 - 财政年份:2023
- 资助金额:
$ 125.57万 - 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
- 批准号:
2748611 - 财政年份:2022
- 资助金额:
$ 125.57万 - 项目类别:
Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
- 批准号:
22K05630 - 财政年份:2022
- 资助金额:
$ 125.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
- 批准号:
10532032 - 财政年份:2022
- 资助金额:
$ 125.57万 - 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
- 批准号:
10525070 - 财政年份:2022
- 资助金额:
$ 125.57万 - 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
- 批准号:
10689017 - 财政年份:2022
- 资助金额:
$ 125.57万 - 项目类别: