Pharmacogenomics of Parkinson's Disease

帕金森病的药物基因组学

• 批准号: 8246511
• 负责人: HAYDEH PAYAMI
• 金额: $ 48.17万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246511
• 关键词: Affect; Age; Aging; Animal Model; Animals; Biological; Caffeine; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell model; Clinical; Clinical Trials; Coffee; Copy Number Polymorphism; Custom; Data; Data Linkages; Development; Disease; Disease Progression; Disease susceptibility; Drosophila genus; Drug Delivery Systems; Environmental Risk Factor; Future; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Techniques; Genotype; Goals; Homologous Gene; Human; Individual; Knowledge; Maps; Modeling; Movement Disorders; Nicotine; Nucleic Acid Regulatory Sequences; Paraquat; Parents; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Population; Prevalence; Research; Research Design; Risk; Risk Reduction; Running; Safety; Screening procedure; Single Nucleotide Polymorphism; Smoking; Testing; Therapeutic; Translating; Weight; analog; base; case control; clinical application; design; disability; disorder prevention; disorder risk; drug development; effective therapy; fly; follow-up; gene discovery; gene environment interaction; gene interaction; genome wide association study; genome-wide; human stem cells; improved; interest; mutant; neurogenetics; novel; patient population; prevent; research study; therapeutic target

PROJECT SUMMARY / ABSTRACT The goal of our research is to translate the advances in genetics into clinical applications and develop novel neuroprotective therapies for Parkinson's disease (PD) targeted on appropriate genotypes for optimal safety and efficacy. PD is a progressive movement disorder that affects 1-2% of the population over the age of 60, and many who are younger. The prevalence of PD is expected to double in the next 20 years and continue to rise with the aging of the population. Symptomatic treatment is available, but progression of disease and complications of therapy cause increasing disability. Presently, there is neither a cure nor an effective treatment that can prevent the disease or delay its onset. Clinical neuroprotective trials have not been successful. PD susceptibility is determined by cumulative and interactive effects of genes and environmental factors; therefore, protection against PD may be possible if the right neuroprotective therapy is targeted on the specific genotypes that promote their beneficial effects. Nicotine and caffeine are neuroprotective in animal models and are robustly associated with reduced risk of PD in humans. We propose to identify the genes that enhance or diminish the effects of smoking/nicotine and caffeine. The genes will in turn become targets for drug development, markers for subdividing patients in clinical trials, and a basis for individualized therapy. We have planned a novel integrated approach, using Drosophila for its powerful genetic techniques and NeuroGenetics Research Consortium (NGRC) for its large well-characterized patient population. The human studies in itself will be comprehensive and include hypothesis-neutral genome-wide studies and hypothesis- driven candidate gene and pathway analyses. The following experiments will be performed: (1) a genome- wide gene-environment interaction study, (2) deficiency screening in the paraquat Drosophila model to identify loci that modify rescue by nicotine and caffeine, and testing the human homologues in NGRC cases and controls, (3) testing human candidate genes and regulatory regions in pathways of interest for their effect on smoking- or coffee-associated PD risk reduction, (4) replication in independent studies. Through these complementary studies, we aim to identify and confirm genetic loci that affect risk of PD through interaction with smoking or coffee, to form the basis for development of predictive markers and therapeutic targets.

项目概要/摘要 我们研究的目标是将遗传学的进展转化为临床应用并开发新的 针对适当基因型的帕金森病 (PD) 神经保护疗法，以实现最佳安全性 和功效。 PD 是一种进行性运动障碍，影响 1-2% 的 60 岁以上人口， 以及许多更年轻的人​​。帕金森病的患病率预计在未来 20 年内将翻一番，并继续增加 随着人口老龄化而上升。对症治疗是可用的，但疾病的进展和 治疗并发症导致残疾增加。目前尚无治愈方法，也没有有效的方法 可以预防疾病或延缓其发作的治疗。尚未进行临床神经保护试验 成功的。 PD易感性由基因和环境的累积和交互作用决定 因素；因此，如果针对帕金森病采取正确的神经保护治疗，则可能可以预防帕金森病。 促进其有益作用的特定基因型。尼古丁和咖啡因对动物具有神经保护作用 模型并与人类 PD 风险降低密切相关。我们建议鉴定基因 增强或减弱吸烟/尼古丁和咖啡因的影响。这些基因将反过来成为目标 药物开发、临床试验中细分患者的标记以及个体化治疗的基础。我们 计划了一种新颖的综合方法，利用果蝇强大的遗传技术和 神经遗传学研究联盟 (NGRC) 拥有大量特征明确的患者群体。人类 研究本身将是全面的，包括假设中立的全基因组研究和假设- 驱动候选基因和通路分析。将进行以下实验：（1）基因组- 广泛的基因-环境相互作用研究，(2) 百草枯果蝇模型中的缺陷筛选，以识别 修改尼古丁和咖啡因救援的位点，并在 NGRC 案例中测试人类同源物和 对照，（3）测试人类候选基因和感兴趣途径中的调控区域对它们的影响 吸烟或咖啡相关的帕金森病风险降低，(4) 在独立研究中重复。通过这些 补充研究，我们的目标是通过相互作用来识别和确认影响 PD 风险的基因位点 与吸烟或咖啡一起，形成预测标记和治疗靶点开发的基础。