Pharmacogenomics of Parkinson's Disease

帕金森病的药物基因组学

• 批准号: 7912610
• 负责人: HAYDEH PAYAMI
• 金额: $ 55.98万
• 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/7912610
• 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; Smoke; 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; public health relevance; research study; therapeutic target

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This study aims to identify genes that interact with environmental compounds that may reduce the risk of developing Parkinson's disease (PD). The new knowledge will enable development of novel personalized therapeutics for PD prevention.

描述（由申请人提供）：我们研究的目标是将遗传学的进展转化为临床应用，并针对适当的基因型开发针对帕金森病（PD）的新型神经保护疗法，以实现最佳的安全性和有效性。 PD 是一种进行性运动障碍，影响 1-2% 的 60 岁以上人口，以及许多年轻人。帕金森病的患病率预计在未来 20 年内将翻一番，并随着人口老龄化而继续上升。可以进行对症治疗，但疾病进展和治疗并发症会导致残疾增加。目前，尚无治愈方法或有效的治疗方法可以预防该疾病或延缓其发病。临床神经保护试验尚未成功。 PD易感性是由基因和环境因素的累积和交互作用决定的；因此，如果正确的神经保护疗法针对能够促进其有益作用的特定基因型，那么就有可能预防帕金森病。尼古丁和咖啡因在动物模型中具有神经保护作用，并且与降低人类患帕金森病的风险密切相关。我们建议鉴定增强或减弱吸烟/尼古丁和咖啡因影响的基因。这些基因反过来将成为药物开发的目标、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，利用果蝇的强大遗传技术和神经遗传学研究联盟 (NGRC) 的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的候选基因和通路分析。将进行以下实验：(1) 全基因组基因-环境相互作用研究，(2) 在百草枯果蝇模型中进行缺陷筛选，以确定改变尼古丁和咖啡因拯救的基因座，并测试 NGRC 病例中的人类同源物和对照，(3) 测试感兴趣途径中的人类候选基因和调控区域对降低吸烟或咖啡相关 PD 风险的影响，(4) 在独立研究中进行复制。通过这些补充研究，我们的目标是识别和确认通过吸烟或咖啡相互作用影响帕金森病风险的基因位点，为开发预测标记和治疗靶点奠定基础。 公共健康相关性：本研究旨在确定与环境化合物相互作用的基因，从而降低患帕金森病 (PD) 的风险。新知识将有助于开发预防帕金森病的新型个性化疗法。