权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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）