Preclinical Pharmacogenomics and Synaptic Biomarkers for Alzheimer's Disease

阿尔茨海默病的临床前药物基因组学和突触生物标志物

• 批准号: 8326645
• 负责人: GREGORY M COLE
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326645
• 关键词: APP-PS1; Address; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apolipoprotein E; Basic Science; Biochemical; Biological Assay; Biological Markers; Brain; Clinic; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Curcumin; Data; Diet; Docosahexaenoic Acids; Economic Burden; Emotional; Epidemiology; Event; Failure; Fish Oils; Fishes; Frequencies; Future; Genetic Risk; Genotype; Human; Immunotherapy; Impaired cognition; Incidence; Inflammation; International; Intervention; Knowledge; Link; Memory impairment; Methods; Mitochondria; Modeling; Molecular Target; Mus; Mutation; Nerve Degeneration; Omega-3 Fatty Acids; Outcome; Pathogenesis; Pathology; Pharmaceutical Preparations; Pharmacogenomics; Plant Roots; Plasma; Prevalence; Prevention; Prevention program; Protein Isoforms; Proteins; Risk; Sampling; Signal Transduction Pathway; Spinach - dietary; Staging; Supplementation; Synapses; Testing; Tg2576; Therapeutic; Translating; Translations; Treatment Efficacy; Treatment outcome; Tumeric; Vaccination; Vaccines; Vegetables; Work; apolipoprotein E-2; apolipoprotein E-4; base; comparative effectiveness; cost; cost effective; design; disorder prevention; drug efficacy; effective therapy; feeding; genetic risk factor; improved; indexing; innovation; interest; lipoate; novel; oxidative damage; pre-clinical; prevent; relating to nervous system; repaired; response; success; tau Proteins; tool; treatment effect; treatment response

DESCRIPTION (provided by applicant): This proposal's broad long-term objectives will address major obstacles to advancing therapeutics and prevention in Alzheimer disease (AD): 1-pharmacogenomics, 2-the molecular targeting of pleiotropic mechanisms implicated in pathogenesis and 3- identifying biomarkers predicting drug efficacy. Despite their limitations, animal models have been fundamental for identifying promising clinical approaches, including the A¿ vaccine and supplementation with omega-3 fatty acids (particularly docosahexaenoic acid, DHA), but success of these approaches may depend on genetic risk (pharmacogenomics) and efficacy may not be robust, if initiated too late. Multiple drugs (cocktails) better target the pleiotropic mechanisms contributing to AD. In this proposal, we focus on ApoE4, the major genetic risk factor for AD. Emerging clinical data suggest a differential ApoE isoform-dependent response to NSAIDs, antioxidants (Hayden et al., 2007; Szekely et al., 2008), DHA or fish (Whalley et al., 2008) and the amyloid vaccine (Salloway et al., 2009). This proposal fulfills a major knowledge gap since, despite the huge impact of ApoE4, preclinical pharmacogenomics studies have not been undertaken. We will characterize the impact of ApoE4 on treatment responses to DHA and determine whether efficacy can be improved by combining DHA with the antioxidant a lipoate (found in vegetables like spinach) or the natural anti-inflammatory drug curcurmin from turmeric root, a combination which we have found to work synergistically and has shown large benefits in APP and tau models, but not tested in relation to ApoE isoform. To overcome these obstacles, we utilize a novel animal model with targeted replacement for human ApoE (isoforms E2, E3 and E4). The advantages of this novel model are that it has synapse loss and cognitive impairment within one year, enabling one to evaluate ApoE isoform dependent effects on treatments. We test passive A¿ vaccination as a "positive control" and to further validate the model since clinical data suggests optimal efficacy only in non ApoE4 carriers. Aim 1) Determine the impact of ApoE4 genotype on limiting DHA protection. Aim 2) Determine if limited DHA efficacy (especially with ApoE4 carriers) is improved with lipoate, curcumin or the combination, Aim 3) Identify ApoE isoform-dependent plasma biomarkers that our data suggest reflect synaptic loss, Aim 4) Identify plasma biomarker responses, that predict treatment efficacy, including immunotherapy. Innovations include identification of novel surrogate biomarkers, improved prevention for ApoE4-carriers and the novel characterization of an animal model suitable for investigating ApoE-genotype treatment interaction. In summary, we address critical barriers to progress in the field of translation by addressing pharmacogenomics, not only challenging existing paradigms for planning future AD prevention programs, but also identifying novel neurodegenerative-dependent plasma biomarkers, essential to overcome inadequate endpoints for AD prevention trials.

描述（由申请人提供）：该提案的广泛长期目标将解决推进阿尔茨海默病（AD）治疗和预防的主要障碍：1-药物基因组学，2-与发病机制有关的多效性机制的分子靶向，3-识别生物标志物尽管有其局限性，动物模型对于确定有前途的临床方法（包括 A¿）至关重要。疫苗和补充 omega-3 脂肪酸（特别是二十二碳六烯酸，DHA），但这些方法的成功可能取决于遗传风险（药物基因组学），如果启动太晚，多种药物（鸡尾酒）可以更好地针对目标，疗效可能不强。导致 AD 的多效性机制 在本提案中，我们重点关注 ApoE4，这是 AD 的主要遗传风险因素，新出现的临床数据表明 ApoE 异构体依赖性反应不同。 NSAIDs、抗氧化剂（Hayden 等人，2007 年；Szekely 等人，2008 年）、DHA 或鱼（Whalley 等人，2008 年）和淀粉样蛋白疫苗（Salloway 等人，2009 年）。因为，尽管 ApoE4 具有巨大影响，但我们尚未进行临床前药物基因组学研究来描述其影响。 ApoE4 对 DHA 的治疗反应，并确定是否可以通过将 DHA 与抗氧化剂硫辛酸（存在于菠菜等蔬菜中）或来自姜黄根的天然抗炎药物姜黄素（我们发现这种组合具有协同作用）来提高疗效，已在 APP 和 tau 模型中显示出巨大的优势，但尚未针对 ApoE 同工型进行测试。为了克服这些障碍，我们利用一种新型动物模型来靶向替代人类 ApoE（同工型）。 E2、E3 和 E4）。这种新模型的优点是它在一年内出现突触损失和认知障碍，使我们能够评估 ApoE 同工型依赖性对治疗的影响。目的 1) 确定 ApoE4 基因型对限制 DHA 保护的影响 目的 2) 确定 DHA 功效是否有限。 ApoE4 携带者）通过硫辛酸、姜黄素或组合得到改善，目标 3）识别 ApoE 同工型依赖性血浆生物标志物，我们的数据表明这些生物标志物反映了突触损失，目标 4) 识别血浆生物标志物反应，预测治疗效果，包括免疫治疗。创新包括识别新型替代生物标志物、改进 ApoE4 携带者的预防措施以及适合研究 ApoE 基因型治疗相互作用的动物模型的新特征。我们通过解决药物基因组学问题来解决翻译领域取得进展的关键障碍，不仅挑战规划未来 AD 预防计划的现有范式，而且还确定新的神经退行性依赖血浆生物标志物，这对于克服不足至关重要AD 预防试验的终点。