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
基本信息
- 批准号:10339430
- 负责人:
- 金额:$ 77.14万
- 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:2020-04-15 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AD transgenic miceAddressAdherenceAffectAlgorithmsAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease therapyAmericanAmyloidAmyloidosisAnimal ModelBayesian ModelingBiological AssayBiological AvailabilityBlood - brain barrier anatomyBrainCase-Control StudiesCause of DeathCellsClinical TrialsCombination Drug TherapyCombined Modality TherapyComplementComplexComputerized Medical RecordComputersDataDatabasesDementiaDiseaseDisease OutcomeDrug CombinationsDrug Delivery SystemsDrug TargetingDrug userEnhancersEvaluationFoundationsGenesGenomeHeritabilityHi-CHippocampus (Brain)HumanHuman GeneticsIn SituIn VitroIncidenceIntelligenceInterdisciplinary StudyInvestmentsKnowledgeLate Onset Alzheimer DiseaseMediatingMedicineMethodologyMicrogliaMolecularMultiomic DataMutateNetwork-basedNeuraxisNeurodegenerative DisordersNeurogliaPathogenesisPatient CarePatientsPenetrationPharmaceutical PreparationsPharmacoepidemiologyPharmacologic SubstancePharmacologyPharmacotherapyPhysiologicalPopulationPositioning AttributePredispositionPreventionPreventive therapyProteinsProteomePublicationsPublishingQuality of lifeRattusRecordsRegimenResearch PersonnelResectedRoleSystemTauopathiesTestingTherapeuticTransgenic AnimalsUnited StatesValidationWorkbasebioinformatics toolbrain endothelial cellbrain tissueclinical efficacyclinically relevantdementia caredrug developmentdrug discoverydrug efficacydrug repurposingdrug testingeffective therapyefficacious treatmentendophenotypefunctional genomicsgenetic architecturegenome wide association studygenome-widegenomic datahuman genome sequencinghuman interactomeimproved outcomein silicoin vivoindividual patientinformatics toolinnovationmouse modelmultiple omicsnovelnovel therapeuticspatient health informationpharmacokinetic modelpopulation basedpromoterrational designresearch and developmentrisk variantside effectsingle cell sequencingsingle-cell RNA sequencingsymptom treatmenttau Proteinstherapeutic developmenttooltranscriptometransgenic model of alzheimer diseasetrial designweb app
项目摘要
Although researchers have conducted more than 400 human trials for potential treatments of Alzheimer’s
disease (AD) in the last two decades, the attrition rate is estimated at over 99%. Furthermore, the “one gene,
one drug, one disease” reductionism-informed paradigm overlooks the inherent complexity of the disease and
continues to challenge drug discovery for AD. The predisposition to AD involves a complex, polygenic, and
pleiotropic genetic architecture. Recent studies have suggested that AD often has common underlying
mechanisms, sharing intermediate endophenotypes with many other complex diseases. These
endophenotypes, such as amyloidosis and tauopathy, have essential roles in many neurodegenerative diseases.
Systematic identification and characterization of novel underlying pathogenesis and disease modules, more so
than mutated genes, will serve as a foundation for generating actionable targets as input for drug repurposing
and rational design of combination therapy in AD. Integration of the genome, transcriptome, proteome, and the
human interactome are essential for such identification. Given our preliminary results, we posit that network-
based identification of novel risk genes and endophenotype modules that share degree between amyloid and
tau offer unexpected opportunities for drug therapy in AD comparing to targeting amyloid and tau separately. To
address the underlying hypothesis, we propose to establish an integrated interdisciplinary research plan with
three specific aims. Aim 1 will explore amyloid and tau-mediated endophenotype modules for AD -- We will test
the network module hypothesis for amyloid and tau using our recently developed Bayesian framework that
integrates multi-omics data (i.e., genome-wide association studies [GWAS] loci, single cell sequencing, and
human brain Hi-C data) and the human interactome. Aim 2 will be capable of searching existing drugs and
combination therapies for AD using network proximity approaches -- We will emphasize the uses of network
proximity approaches (i.e., Genome-wide Positioning Systems network [GPSnet]) to identify repurposable drugs
and efficacious combination regimens. This will be accomplished by integrating AD endophenotype module
findings, public drug-target databases, the human interactome, and the large-scale patient longitudinal Claims-
Electronic Medical Record data (over 200 million patients from the MarketScan database). Aim 3 will evaluate
brain penetration and target network engagement for repurposable drugs -- We will use the humanized in
vitro blood-brain barrier, resected brain tissues (ex vivo/in situ), and transgenic AD models (i.e., TgF344-AD rats)
to experimentally evaluate brain penetration and target network engagement. Evaluation will be based upon
network proximity to the AD-related endophenotype modules that are relevant to maximizing efficacy and to
minimizing side effects. The successful completion of this project will offer powerful network methodologies and
bioinformatics tools for prediction and population-based validation of in silico drug repurposing. It will also allow
for the identification of novel repurposable drugs and clinically relevant combination therapies toward AD trials.
尽管研究人员已经进行了400多项人体试验,以寻找治疗阿尔茨海默氏症的潜在方法,
在过去的二十年中,疾病(AD)的流失率估计超过99%。此外,“一个基因,
“一种药物,一种疾病”的简化主义范式忽视了疾病的内在复杂性,
继续挑战AD的药物发现。AD的易感性涉及一个复杂的、多基因的、
多效性遗传结构最近的研究表明,AD通常具有共同的潜在
与许多其他复杂疾病共享中间内在表型。这些
内源性表型如淀粉样变性和tau蛋白病在许多神经变性疾病中具有重要作用。
系统识别和表征新的潜在发病机制和疾病模块,更重要的是
而不是突变基因,将作为产生可操作目标的基础,作为药物再利用的输入
并合理设计AD的联合治疗方案。基因组、转录组、蛋白质组和
人类相互作用组对于这种识别至关重要。根据我们的初步结果,我们对该网络进行了优化-
基于新的风险基因和内表型模块的鉴定,
与分别靶向淀粉样蛋白和tau相比,tau为AD的药物治疗提供了意想不到的机会。到
解决基本假设,我们建议建立一个综合的跨学科研究计划,
三个具体目标。目的1将探索淀粉样蛋白和tau蛋白介导的AD内表型模块-我们将测试
使用我们最近开发的贝叶斯框架,对淀粉样蛋白和tau进行网络模块假设,
集成多组学数据(即,全基因组关联研究[GWAS]基因座,单细胞测序,
人脑Hi-C数据)和人类相互作用组。Aim 2将能够搜索现有的药物,
使用网络邻近方法的AD联合治疗-我们将强调网络邻近方法的使用。
邻近方法(即,全基因组定位系统网络[GPSnet])来识别可重复使用的药物
和有效的组合方案。这将通过整合AD内表型模块来实现
研究结果、公共药物靶点数据库、人类相互作用组和大规模患者纵向声明-
电子病历数据(MarketScan数据库中的2亿多名患者)。目标3将评估
大脑渗透和目标网络参与可重复利用的药物-我们将使用人性化的,
体外血脑屏障、切除的脑组织(离体/原位)和转基因AD模型(即,TgF 344-AD大鼠)
实验性地评估大脑渗透和目标网络参与。评估将基于
与AD相关内表型模块的网络接近度,这些模块与最大化疗效相关,
使副作用最小化。该项目的成功完成将提供强大的网络方法,
生物信息学工具,用于预测和基于人群的计算机药物再利用验证。它还将允许
用于识别新的可重复利用的药物和临床相关的组合疗法,以进行AD试验。
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:
$ 77.14万 - 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:
$ 77.14万 - 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:
$ 77.14万 - 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:
10418459 - 财政年份:2022
- 资助金额:
$ 77.14万 - 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:
$ 77.14万 - 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:
$ 77.14万 - 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:
$ 77.14万 - 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:
$ 77.14万 - 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:
$ 77.14万 - 项目类别:
相似海外基金
Pharmacy-led Transitions of Care Intervention to Address System-Level Barriers and Improve Medication Adherence in Socioeconomically Disadvantaged Populations
药房主导的护理干预转型,以解决系统层面的障碍并提高社会经济弱势群体的药物依从性
- 批准号:
10594350 - 财政年份:2023
- 资助金额:
$ 77.14万 - 项目类别:
Evaluating Centralizing Interventions to Address Low Adherence to Lung Cancer Screening Follow-up in Decentralized Settings
评估集中干预措施,以解决分散环境中肺癌筛查随访依从性低的问题
- 批准号:
10738120 - 财政年份:2023
- 资助金额:
$ 77.14万 - 项目类别:
Suubi-Mhealth: A mobile health intervention to address depression and improve ART adherence among Youth living with HIV (YLHIV) in Uganda
Suubi-Mhealth:一种移动健康干预措施,旨在解决乌干达艾滋病毒感染者 (YLHIV) 青少年的抑郁症问题并提高抗逆转录病毒疗法的依从性
- 批准号:
10526768 - 财政年份:2022
- 资助金额:
$ 77.14万 - 项目类别:
Suubi-Mhealth: A mobile health intervention to address depression and improve ART adherence among Youth living with HIV (YLHIV) in Uganda
Suubi-Mhealth:一种移动健康干预措施,旨在解决乌干达艾滋病毒感染者 (YLHIV) 青少年的抑郁症问题并提高抗逆转录病毒疗法的依从性
- 批准号:
10701072 - 财政年份:2022
- 资助金额:
$ 77.14万 - 项目类别:
A behavioral intervention for Black men who have sex with men and live with HIV to address intersectional stigma and improve antiretroviral therapy adherence
针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
- 批准号:
10679092 - 财政年份:2021
- 资助金额:
$ 77.14万 - 项目类别:
A behavioral intervention for Black men who have sex with men and live with HIV to address intersectional stigma and improve antiretroviral therapy adherence
针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
- 批准号:
10432133 - 财政年份:2021
- 资助金额:
$ 77.14万 - 项目类别:
A behavioral intervention for Black men who have sex with men and live with HIV to address intersectional stigma and improve antiretroviral therapy adherence
针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
- 批准号:
10327065 - 财政年份:2021
- 资助金额:
$ 77.14万 - 项目类别:
Leveraging Technology to Address Access and Adherence to Conventional Hospital-Based Pulmonary Rehabilitation in Veterans with COPD
利用技术解决慢性阻塞性肺病退伍军人接受和坚持传统医院肺康复的问题
- 批准号:
10377366 - 财政年份:2019
- 资助金额:
$ 77.14万 - 项目类别:
Leveraging Technology to Address Access and Adherence to Conventional Hospital-Based Pulmonary Rehabilitation in Veterans with COPD
利用技术解决慢性阻塞性肺病退伍军人接受和坚持传统医院肺康复的问题
- 批准号:
10574496 - 财政年份:2019
- 资助金额:
$ 77.14万 - 项目类别:
Targeted interventions to address the multi-level effects of gender-based violence on PrEP uptake and adherence among adolescent girls and young women in Kenya
有针对性的干预措施,以解决性别暴力对肯尼亚少女和年轻妇女接受和坚持 PrEP 的多层面影响
- 批准号:
9403567 - 财政年份:2017
- 资助金额:
$ 77.14万 - 项目类别: