Translating in vivo drug screens to Alzheimer's patients with a pharmaco-epidemiological approach
利用药物流行病学方法将体内药物筛选应用于阿尔茨海默病患者
基本信息
- 批准号:10727993
- 负责人:
- 金额:$ 9.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAgingAgreementAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAlzheimer&aposs disease therapyAmyloid beta-ProteinArthritisAutomobile DrivingAwardBiological AssayBiology of AgingCaenorhabditis elegansCase/Control StudiesCategoriesCell Culture TechniquesChronicClinical TrialsCrohn&aposs diseaseDataData SetDatabasesDevelopmentDiseaseDrug ScreeningDrug TargetingDrug usageElderlyEpidemiologistEpidemiologyEventFDA approvedFeasibility StudiesFunctional disorderFundingFutureGeriatricsGoalsHumanImpaired cognitionInflammationInflammatoryInterleukin-6InvestmentsKnowledgeLibrariesLongevityMedicareMentorsMethodsMicrogliaModelingMusMuscleMyelogenousNeurodegenerative DisordersOutcome MeasurePathologyPathway interactionsPatientsPeptidesPharmaceutical PreparationsPharmacoepidemiologyPharmacologic SubstancePhenothiazinesPhenotypePilot ProjectsPioglitazonePopulationProbabilityProcessProtective AgentsProteinsProtocols documentationPsoriasisRecording of previous eventsResearchResearch PersonnelRiskRisk ReductionSafetySamplingSourceSpecialistTNF geneTechnologyTestingTherapeuticTimeToxic effectTransgenic OrganismsTranslatingTranslationsUnited States Centers for Medicare and Medicaid Servicesabeta toxicityadalimumabage relatedbeneficiarycareerclinically significantcytokinedemographicsdesigndisease diagnosisdrug candidatedrug repurposingexperiencegenome wide association studyhazardhealth recordhigh-throughput drug screeningimprovedin vivoinnovationinterestmedical schoolsmodel organismmonocytenovelpharmacologicpopulation healthprotective effectproteotoxicitysafety assessmentscreeningsymptom treatmenttau Proteins
项目摘要
Project Summary/Abstract (30 lines)
We hypothesize that drug trials, in Alzheimer's disease (AD) have failed in humans because AD entails both
proteotoxicity (involving at least Aß and tau) AND microglial activity (clearly demonstrated by GWAS studies),
probably with hypersecretion of inflammatory cytokines. Successful treatments will probably require drugs that
ameliorate proteotoxicity AND microglial hypersecretion of cytokines, rather than targeting levels of a single
protein or peptide. We propose that a phenotype-based screening approach is more likely to lead to overall
successful therapies for AD and aging related diseases in general. Although 5 drugs are approved to treat AD,
they only treat symptoms, not causes of AD, and it is widely agreed that the clinical significance of these drugs
is modest at best. An increasing number of pharmaceutical companies have abandoned the search for
treatments for AD. We therefore developed an innovative high-throughput drug screening platform and
conducted two unparalleled high-throughput drug-repurposing screens for their ability to protect against Aß
toxicity in Caenorhabditis elegans as a model for the more general process of proteotoxicity in vivo. In
subsequent studies, the most protective drugs in C. elegans were then rescreened in microglia for their ability to
reduce cytokine release (primarily TNF-alpha and IL-6). These screens led us to prioritize approximately 50 FDA-
approved drugs that were protective in these phenotypic assays. The objective of the presently proposed studies
is to evaluate if treatment with these FDA-approved drugs (or drugs in similar categories) reduce the risk of AD.
We propose to use population-level administrative claims data collected from the Centers for Medicare and
Medicaid Services (CMS) to assess if FDA-approved drugs that are protective in a C. elegans model of AD also
lower the risk for AD and related dementia in humans. The proposed project is an observational retrospective
pharmaco-epidemiological case-control study. The team will use a cox proportional hazard regression to obtain
hazard ratios of AD associated with each prioritized FDA-approved drug. Data will be acquired from CMS to
cover 5 consecutive years and all models will be fitted and adjusted to the covariates. The end goal of the study
is to identify drugs to be repurposed to treat AD and related dementia and to accumulate strong epidemiological
evidence in addition to the existing evidence from the model organism C. elegans and cell culture studies.
This transdisciplinary research between aging biologists, geriatricians, and epidemiologists will yield data and
experience essential to launch the applicant’s subsequent research and independent research career. The
results of the proposed study will be further compared with data from other population health records and
incorporated into the design of a future clinical trial. The research will take place at the Icahn School of Medicine
at Mount Sinai, which has a leading Geriatrics Department and world experts in pharmaco- epidemiology.
项目摘要/摘要(30行)
项目成果
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