Pharmacogenetics of donepezil in mild cognitively impaired patients

轻度认知障碍患者多奈哌齐的药物遗传学

基本信息

批准号：
9247112
负责人：
Sophie Sokolow
金额：
$ 17.34万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247112
关键词：
Acetylcholinesterase Inhibitors Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Apolipoproteins Award Bioinformatics Biological Biomedical Research Biometry Candidate Disease Gene Clinical Clinical Research Clinical Treatment Clinical Trials Cognition Cognitive Data Data Set Dementia Development Diagnosis Disease Disease Progression Disease susceptibility Future Genetic Genetic Markers Genetic Polymorphism Genetic Variation Genetic screening method Genome Genomics Genotype Impaired cognition Individual Investigation Label Lead Linear Regressions Literature Los Angeles Measures Memory Memory impairment Mentored Patient-Oriented Research Career Development Award Mentors Modeling Molecular Biology Mus Neurobehavioral Manifestations Neurobiology Neuropsychological Tests Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacology Pharmacotherapy Pharmacy facility Phenotype Play Population Sciences Research Research Institute Research Personnel Resources Risk Role School Nursing Science Single Nucleotide Polymorphism Sum Susceptibility Gene Syndrome Testing Therapeutic Trail Making Test Training United States National Institutes of Health Vitamin E age related amnestic mild cognitive impairment base career clinical practice cognitive function collaborative environment common treatment cooperative study design donepezil executive function follow-up genetic predictors genetic risk factor genome wide association study imaging biomarker interpatient variability memory recall mental state mild cognitive impairment neuroimaging neuropsychiatry normal aging novel novel therapeutics patient oriented research phenomenological models pre-clinical programs public health relevance response secondary analysis skills statistics symptom treatment trait translational genomics treatment response whole genome

项目摘要

DESCRIPTION (provided by applicant): The purpose of this application for a K23 award is to provide additional training to Dr. Sokolow to establish herself as a successful independent investigator in patient-oriented research focusing on the pharmacogenomics (PGX) of Alzheimer's Disease (AD). Dr. Sokolow's academic background includes an advanced degree in pharmacy practice and a doctorate in Biomedical Sciences with specialization in molecular biology and mouse genetics. For the past seven years, her research program at the UCLA School of Nursing has focused on the neurobiology of AD. Her training plan includes a cross-training in bioinformatics, biostatistics and statistical genomics. In addition to her training pla, she has assembled an outstanding mentoring team with expertise in clinical phenomenology of AD, genome-wide association studies (GWAS) and PGX. The collaborative environment of the UCLA School of Nursing, the UCLA Mary S. Easton Center for AD Research and the Institute for Translational Genomics and Population Sciences - Los Angeles Biomedical Research Institute is ideal for developing her new research program focusing on the investigation of genetic factors affecting the response to donepezil (DPZ) in MCI individuals. MCI is a syndrome characterized by a memory deficit which differs from normal age-related changes in memory and dementia. There is no pharmacotherapy approved for the treatment of cognitive symptoms in MCI patients; however DPZ is the most commonly prescribed medication for this disorder. Existing neuropsychological testing and GWAS data collected from 3 previously conducted studies [i.e. Alzheimer's Disease Neuroimaging Initiative study (ADNI); Alzheimer's Disease Cooperative Study (ADCS) trial of MCI and the Imaging and Genetic Biomarkers for Alzheimer's Disease study (ImaGene)] will be used to address 3 complementary specific aims. In Aim 1, we will impute the existing GWAS against the 1000 genome project and we will perform association studies to test the interactions between DPZ response and candidate genetic polymorphisms associated with AD susceptibility/endopehenotype and/or with DPZ response in AD. DPZ response will first be estimated with existing Clinical Dementia Rating sum of boxes scores. Follow-up of the top PGX markers will be assessed with 5 other measures of cognition and executive function. In Aim 2, we will use the same resources and we will apply pathway-based association analyses of DPZ response in MCI to identify new PGX markers. In Aim 3, we expect to validate the associations between DPZ response and the strongest candidate for the actual predisposing SNPs at the top genetic loci discovered in Aims 1&2 using existing Whole-genome sequence (WGS) data from ADNI study. Overall, we expect to demonstrate the usefulness of PGX testing in clinical practice and in clinical trials to identify the individuals who are most liely to benefit from the pharmacotherapy. At the conclusion of this award, Dr. Sokolow will have the necessary skill sets to compete effectively for future NIH support and to propel her to an independent career in AD PGX.

描述（由应用程序提供）：本申请授予K23奖的目的是为Sokolow博士提供额外的培训，以确立自己的成功的独立研究者，以患者为导向的研究，重点是阿尔茨海默氏病（AD）的药物基因组学（PGX）。索科洛（Sokolow）博士的学术背景包括具有分子生物学和小鼠遗传学专业化的生物医学科学博士学位和博士学位。在过去的七年中，她在加州大学洛杉矶分校护理学院的研究计划集中在AD的神经生物学上。她的培训计划包括生物信息学，生物统计学和统计基因组学的交叉训练。除了训练PLA外，她还组建了一支杰出的心理团队，该团队在AD，全基因组协会研究（GWAS）和PGX方面具有专业知识。 UCLA护理学院，UCLA Mary S. Easton AD研究中心和转化基因组学和人口科学研究所 - 洛杉矶生物医学研究所的合作环境非常适合开发她的新研究计划，重点是研究对MCI个人的遗传因素的调查，这些研究影响了对MCI个人的遗传因素。 MCI是一种综合征，其特征是记忆力不足，其与年龄相关的记忆变化不同，并且没有药物治疗MCI患者的认知症状。但是，DPZ是该疾病最常见的药物。从先前进行的3项研究中收集的现有神经心理学测试和GWAS数据[即阿尔茨海默氏病神经影像学倡议研究（ADNI）；阿尔茨海默氏病合作研究（ADCS）对阿尔茨海默氏病研究（Imagene）的成像和遗传生物标志物的试验（Imagene）将用于解决3个完整的特定目标。在AIM 1中，我们将将现有的GWA归因于1000个基因组项目，并将进行关联研究，以测试DPZ响应与候选遗传多态性与AD易感性/内型型和/或与AD中DPZ响应有关的候选遗传多态性之间的相互作用。 DPZ响应将首先使用现有的临床痴呆率评分总和估计。顶级PGX标记的随访将通过其他5种认知和执行功能的措施进行评估。在AIM 2中，我们将使用相同的资源，并将应用MCI中DPZ响应的基于途径的关联分析来识别新的PGX标记。在AIM 3中，我们希望使用ADNI研究中现有的全基因组序列（WGS）数据在AIMS 1和2中发现的最高遗传基因座的实际易感性SNP验证DPZ响应与强大易感性SNP之间的关联。总体而言，我们预计将证明PGX测试在临床实践和临床试验中的有用性，以确定最骗人的人，以从药物治疗中受益。在该奖项结束时，Sokolow博士将拥有必要的技能，以有效地竞争未来的NIH支持，并将她从事AD PGX的独立职业。