TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease
基于 TREM2 基因型的阿尔茨海默病药物再利用和联合治疗设计
基本信息
- 批准号:10418459
- 负责人:
- 金额:$ 83.15万
- 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:2022-07-15 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAKT inhibitionAffectAfrican AmericanAgeAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAmericanAmyloidAmyloid beta-ProteinAnti-Inflammatory AgentsAreaAsthmaAttentionBiologyBrainCell LineCell NucleusCellsCerebrumClinicClinicalClinical TrialsCombination Drug TherapyCombined Modality TherapyCommunicationComputersDataDatabasesDevelopmentDiseaseDisease OutcomeDisease ProgressionDisease associated microgliaDoseDrug CombinationsDrug ScreeningDrug TargetingDrug usageElectronic Health RecordGene TargetingGenerationsGenesGeneticGenetic TranscriptionGenomeGenomicsGenotypeHealth systemHumanHuman GeneticsImmuneIncidenceInflammationInflammatoryIntelligenceInterventionInvestigationKnock-in MouseKnowledge PortalLate Onset Alzheimer DiseaseLeadLinkMachine LearningMedicineMethodologyMethodsMicrogliaMolecularMolecular TargetMusMutationNatureNerve DegenerationNetwork-basedNeurodegenerative DisordersNeurogliaNew York CityObservational StudyOrganoidsPathogenesisPatientsPenetrationPersonsPharmaceutical PreparationsPharmacoepidemiologyPharmacologyPharmacotherapyPlayPopulationProcessPropertyResearchRiskRoleSignal TransductionSourceSystemSystems BiologyTREM2 geneTauopathiesTestingToxic effectUnited StatesValidationVariantanalytical toolbasebench to bedsidebrain endothelial cellcell typeclinical efficacycohortdeep learningdrug candidatedrug discoverydrug repurposingdrug testingexperimental studyfluticasonegenome-widegenomic datahuman diseasein vitro Assayinduced pluripotent stem cellknowledge graphmetropolitanmolecular targeted therapiesmouse modelmultimodalitymultiple omicsmutantneuroinflammationnovelpopulation basedpreclinical efficacypreventrisk variantside effectsuccesstargeted treatmenttau Proteinstherapy designtranscriptome sequencingtreatment effecttrial design
项目摘要
PROJECT SUMMARY
The cumulative evidence indicates neuro-inflammation play crucial roles in Alzheimer’s disease (AD) and anti-
inflammatory agents (i.e., microglia-targeted therapies) show potential treatments for AD. The treatment
window for microglia-targeted therapies may at least be open later in AD due to the nature of microglial biology.
If amyloid-β is the trigger for AD, and tau is the executioner, then microglia are accelerators of disease
progression. Microglia-targeted approaches have a better chance of success in mild to moderate disease
compared to anti-amyloid therapies that have to prevent the trigger early in AD. Among the microglial genes,
triggering receptor expressed on myeloid cells 2 (TREM2) has received much attention because a hemizygous
R47H variant of TREM2 (TREM2R47H) increases the AD risk by 2-7 folds in various populations, including African
American. Our preliminary single-nucleus RNA-sequencing (snRNAseq) study identified disease-associated
microglia (DAM) with enhanced AD pro-inflammatory signatures (i.e., activation of Akt-signaling) associated with
the TREM2R47H variant and pharmacological Akt inhibition reversed the TREM2R47H induced inflammation,
showing proof-of-concept of TREM2R47H targeted drug discovery in AD. Using multimodal snRNAseq analysis,
we identified two approved anti-inflammatory asthma drugs (fluticasone and mometasone) that were predicted
to modulate DAM molecular networks are associated with a reduced incidence of AD in electronic health record
(EHR) data of 7 million patients. We therefore posit that understanding how the AD-linked mutations (i.e.,
TREM2R47H) enhance microglial toxicity could lead to understanding how microglia become maladaptive/toxic
and development of microglia-targeted therapeutic strategy for late-onset sporadic AD in general. This
application calls for novel microglia-targeted drug repurposing and combination therapies for AD using our
well-established multi-omics and deep learning-based EHR approaches, and functional observations in AD
patient-induced pluripotent stem cells (iPSCs), cerebral organoids, and mouse models, with three specific Aims.
Aim 1 will test the TREM2R47H informed microglia-targeted therapeutic hypothesis for identifying cell type-specific
molecular drivers/networks, repurposable drugs, and combination therapies for AD using multi-omics evidence
aggregation. These analyses will leverage our existing snRNAseq data (n = 24 TREM2R47H and n = 23 common
variant (CV)-TREM2 with matched age, AD pathology and APOE genotypes) and public genomic data from the
AD knowledge portal. Aim 2 will identify repurposable drugs and combination therapies using high-throughput
EHR-based hypothesis generation and sequential deep learning-based propensity score matching approaches.
We will leverage de-identified EHRs from the INSIGHT networks (~11 million patients across New York City’s 5
health systems and the greater metropolitan area). Aim 3 will screen, test and validate drugs using AD patient-
derived iPSC lines carrying TREM2R47H in conjunction with cerebral organoid and mouse models. The successful
completion of this project will offer a viable strategy to move AD drug repurposing from bench to bedside rapidly.
1
项目总结
累积的证据表明,神经炎症在阿尔茨海默病(AD)和抗阿尔茨海默病(AD)中起着至关重要的作用。
炎症剂(即小胶质细胞靶向治疗)显示了治疗AD的潜在方法。治疗方法
由于小胶质细胞生物学的性质,小胶质细胞靶向治疗的窗口至少可能在AD晚些时候打开。
如果淀粉样蛋白-β是AD的触发因素,tau是刽子手,那么小胶质细胞就是疾病的加速器
进步。针对小胶质细胞的方法在轻到中度疾病中有更好的成功机会
与必须在AD早期预防触发的抗淀粉样蛋白治疗相比。在小胶质细胞基因中,
触发髓系细胞上表达的受体2(TREM2)已受到广泛关注,因为半合子
TREM2的R47H变异(TREM2R47H)在包括非洲人在内的不同人群中使AD风险增加2-7倍
美国人。我们的初步单核RNA测序(SnRNAseq)研究确定了与疾病相关的
具有增强的AD促炎信号(即激活Akt信号)的小胶质细胞(DAM)与
TREM2R47H变异体和药理Akt抑制逆转TREM2R47H诱导的炎症,
展示了TREM2R47H在AD中靶向药物发现的概念证明。使用多模式SnRNAseq分析,
我们确定了两种已获批准的抗炎哮喘药物(氟替卡松和莫美松)。
调制DAM分子网络与电子健康记录中AD发病率的降低有关
(EHR)700万患者的数据。因此,我们假设,对AD相关突变(即,
TREM2R47H)增强小胶质细胞毒性可能有助于理解小胶质细胞如何变得适应不良/毒性
以及开发针对迟发性散发性AD的小胶质细胞靶向治疗策略。这
应用需要新的小胶质细胞靶向药物再利用和联合疗法治疗AD
成熟的基于多组学和深度学习的EHR方法,以及AD的功能观察
患者诱导的多能干细胞(IPSCs)、脑器官和小鼠模型,有三个特定的目标。
Aim 1将测试TREM2R47H信息的小胶质细胞靶向治疗假说,以确定细胞类型特异性
基于多组学证据的AD分子驱动因素/网络、可再利用药物和联合疗法
聚合。这些分析将利用我们现有的SnRNAseq数据(n=24个TREM2R47H和n=23个常见
变异(CV)-具有匹配的年龄、AD病理和APOE基因型的TREM2)和来自
广告知识门户。AIM 2将利用高通量确定可重复使用的药物和联合疗法
基于EHR的假设生成和基于序列深度学习的倾向得分匹配方法。
我们将利用Insight网络中已取消身份的EHR(纽约市5个地区约1,100万名患者
卫生系统和大都市地区)。AIM 3将使用AD患者筛选、测试和验证药物-
衍生的携带TREM2R47H的IPSC系与脑器官和小鼠模型相结合。成功者
该项目的完成将提供一种可行的战略,将AD药物的再利用从工作台迅速转移到床边。
1
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 }}
Feixiong Cheng其他文献
Feixiong Cheng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('Feixiong Cheng', 18)}}的其他基金
Alzheimer's Disease and Related Dementia-like Sequelae of SARS-CoV-2 Infection: Virus-Host Interactome, Neuropathobiology, and Drug Repurposing
阿尔茨海默病和 SARS-CoV-2 感染的相关痴呆样后遗症:病毒-宿主相互作用组、神经病理生物学和药物再利用
- 批准号:
10661931 - 财政年份:2023
- 资助金额:
$ 83.15万 - 项目类别:
Microglial Activation and Inflammatory Endophenotypes Underlying Sex Differences of Alzheimer’s Disease
阿尔茨海默病性别差异背后的小胶质细胞激活和炎症内表型
- 批准号:
10755779 - 财政年份:2023
- 资助金额:
$ 83.15万 - 项目类别:
Precision Medicine Digital Twins for Alzheimer’s Target and Drug Discovery and Longevity
用于阿尔茨海默氏症靶点和药物发现及长寿的精准医学数字孪生
- 批准号:
10727793 - 财政年份:2023
- 资助金额:
$ 83.15万 - 项目类别:
TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease
基于 TREM2 基因型的阿尔茨海默病药物再利用和联合治疗设计
- 批准号:
10665664 - 财政年份:2022
- 资助金额:
$ 83.15万 - 项目类别:
Endophenotype Network-based Approaches to Prediction and Population-based Validation of In Silico Drug Repurposing for Alzheimer's Disease
基于内表型网络的方法对阿尔茨海默病的计算机药物重新利用进行预测和基于群体的验证
- 批准号:
10409194 - 财政年份:2020
- 资助金额:
$ 83.15万 - 项目类别:
Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease
基于内表型网络的方法对阿尔茨海默病的计算机药物重新利用进行预测和基于群体的验证
- 批准号:
10339430 - 财政年份:2020
- 资助金额:
$ 83.15万 - 项目类别:
Endophenotype Network-based Approaches to Prediction and Population-based Validation of in Silico Drug Repurposing for Alzheimers Disease
基于内表型网络的方法对阿尔茨海默病的计算机药物重新利用进行预测和基于群体的验证
- 批准号:
10569077 - 财政年份:2020
- 资助金额:
$ 83.15万 - 项目类别:
An individualized network medicine infrastructure for precision cardio-oncology
用于精准心脏肿瘤学的个性化网络医学基础设施
- 批准号:
9755498 - 财政年份:2017
- 资助金额:
$ 83.15万 - 项目类别:
An individualized network medicine infrastructure for precision cardio-oncology
用于精准心脏肿瘤学的个性化网络医学基础设施
- 批准号:
9371272 - 财政年份:2017
- 资助金额:
$ 83.15万 - 项目类别:
相似海外基金
Elucidating resistance to AKT inhibition in metastatic breast cancer
阐明转移性乳腺癌对 AKT 抑制的耐药性
- 批准号:
2440937 - 财政年份:2020
- 资助金额:
$ 83.15万 - 项目类别:
Studentship
The Risk of Novel AKT Inhibition on Lethal Neuroendocrine Prostate Cancer Development
新型 AKT 抑制对致死性神经内分泌前列腺癌发展的风险
- 批准号:
350042 - 财政年份:2015
- 资助金额:
$ 83.15万 - 项目类别:
Studentship Programs
Mechanistic studies of cancer cell adaptive response to PI3K/AKT inhibition
癌细胞对 PI3K/AKT 抑制的适应性反应的机制研究
- 批准号:
9272854 - 财政年份:2015
- 资助金额:
$ 83.15万 - 项目类别:
Targeting RAS signaling with CDK and AKT inhibition in pancreatic cancer
通过 CDK 和 AKT 抑制作用靶向胰腺癌中的 RAS 信号传导
- 批准号:
8581465 - 财政年份:2013
- 资助金额:
$ 83.15万 - 项目类别:
Targeting RAS signaling with CDK and AKT inhibition in pancreatic cancer
通过 CDK 和 AKT 抑制作用靶向胰腺癌中的 RAS 信号传导
- 批准号:
8692694 - 财政年份:2013
- 资助金额:
$ 83.15万 - 项目类别: