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：
Rachel Litke
金额：
$ 9.46万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
https://reporter.nih.gov/project-details/10727993
关键词：
Address Aging Agreement Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid beta-Protein Arthritis Automobile Driving Award Biological Assay Biology of Aging Caenorhabditis elegans Case/Control Studies Categories Cell Culture Techniques Chronic Clinical Trials Crohn&apos s disease Data Data Set Databases Development Disease Drug Screening Drug Targeting Drug usage Elderly Epidemiologist Epidemiology Event FDA approved Feasibility Studies Functional disorder Funding Future Geriatrics Goals Human Impaired cognition Inflammation Inflammatory Interleukin-6 Investments Knowledge Libraries Longevity Medicare Mentors Methods Microglia Modeling Mus Muscle Myelogenous Neurodegenerative Disorders Outcome Measure Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacoepidemiology Pharmacologic Substance Phenothiazines Phenotype Pilot Projects Pioglitazone Population Probability Process Protective Agents Proteins Protocols documentation Psoriasis Recording of previous events Research Research Personnel Risk Risk Reduction Safety Sampling Source Specialist TNF gene Technology Testing Therapeutic Time Toxic effect Transgenic Organisms Translating Translations United States Centers for Medicare and Medicaid Services abeta toxicity adalimumab age related beneficiary career clinically significant cytokine demographics design disease diagnosis drug candidate drug repurposing experience genome wide association study hazard health record high-throughput drug screening improved in vivo innovation interest medical schools model organism monocyte novel pharmacologic population health protective effect proteotoxicity safety assessment screening symptom treatment tau Proteins

Address Aging Agreement Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid beta-Protein Arthritis Automobile Driving Award Biological Assay Biology of Aging Caenorhabditis elegans Case/Control Studies Categories Cell Culture Techniques Chronic Clinical Trials Crohn&apos s disease Data Data Set Databases Development Disease Drug Screening Drug Targeting Drug usage Elderly Epidemiologist Epidemiology Event FDA approved Feasibility Studies Functional disorder Funding Future Geriatrics Goals Human Impaired cognition Inflammation Inflammatory Interleukin-6 Investments Knowledge Libraries Longevity Medicare Mentors Methods Microglia Modeling Mus Muscle Myelogenous Neurodegenerative Disorders Outcome Measure Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacoepidemiology Pharmacologic Substance Phenothiazines Phenotype Pilot Projects Pioglitazone Population Probability Process Protective Agents Proteins Protocols documentation Psoriasis Recording of previous events Research Research Personnel Risk Risk Reduction Safety Sampling Source Specialist TNF gene Technology Testing Therapeutic Time Toxic effect Transgenic Organisms Translating Translations United States Centers for Medicare and Medicaid Services abeta toxicity adalimumab age related beneficiary career clinically significant cytokine demographics design disease diagnosis drug candidate drug repurposing experience genome wide association study hazard health record high-throughput drug screening improved in vivo innovation interest medical schools model organism monocyte novel pharmacologic population health protective effect proteotoxicity safety assessment screening symptom treatment tau Proteins

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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）我们假设在阿尔茨海默氏病（AD）中进行的药物试验在人类中失败了，因为AD实体都是蛋白毒性（至少涉及Aß和TAU）和小胶质细胞活性（由GWAS研究清楚地证明），成功的治疗可能需要药物改善细胞因子的蛋白质毒性和小胶质细胞过度分泌，而不是靶向单个因子的水平蛋白质或胡椒。我们建议基于表型的筛选方法更有可能导致总体一般来说，针对广告和衰老有关的疾病的成功疗法。尽管批准了5种药物来治疗AD，但是他们只治疗症状，而不是AD的原因，并且普遍认为这些药物的临床意义充其量是谦虚的。越来越多的制药公司放弃了寻找广告的治疗方法。因此，我们开发了一个创新的高通量药物筛查平台和进行了两个无与伦比的高通量药物固定屏幕，以防止Aß 秀丽隐杆线虫中的毒性是体内蛋白质毒性更一般过程的模型。在随后的研究，秀丽隐杆线虫中最受保护的药物随后在小胶质细胞中被重新覆盖，以便其能力减少细胞因子释放（主要是TNF-Alpha和IL-6）。这些屏幕使我们优先考虑大约50 fda- 在这些表型测定中受到保护的批准药物。目前提出的研究的目的是为了评估这些FDA批准的药物（或类似类别的药物）是否降低了AD的风险。我们建议使用从Medicare中心收集的人口级行政索赔数据， Medicaid Services（CMS）评估在AD的C.秀丽隐杆线虫模型中受到保护的FDA批准药物是否也降低人类AD和相关痴呆的风险。拟议的项目是一个观察性的回顾药物 - 流行病学病例对照研究。团队将使用COX比例危害回归来获得与每种优先FDA批准的药物相关的AD危险比。数据将从CMS获取连续5年覆盖，所有模型将安装并调整到协变量。研究的最终目标是要确定要重新使用的药物以治疗AD和相关痴呆并积累强烈的流行病学除了来自模型有机体C.秀丽隐杆线虫和细胞培养研究的现有证据之外。老龄化生物学家，老年医生和流行病学家之间的跨学科研究将产生数据和启动申请人随后的研究和独立研究职业必不可少的经验。拟议研究的结果将与其他人口健康记录的数据进行比较并入将来的临床试验设计。该研究将在伊坎医学院进行在西奈山（Mount Sinai），拥有领先的老年医学系和药物流行病学的世界专家。