Antiretroviral pharmacogenomics, pharmacokinetics and toxicity in neuroAIDS

神经艾滋病中的抗逆转录病毒药物基因组学、药代动力学和毒性

基本信息

批准号：
8860246
负责人：
Qing Ma
金额：
$ 11.98万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8860246
关键词：
Animal Model Anti-Retroviral Agents Applications Grants Area Atazanavir Award Bioinformatics Biological Models Brain Buffaloes Candidate Disease Gene China Chinese People Clinical Clinical Investigator Clinical Trials Comorbidity Control Groups DNA Data Development Disease Progression Disease model Dose Drug Kinetics Environment Enzymes Etiology Evaluation Exhibits Foundations Gene Expression Gene Expression Profiling Genes Genetic Genetic Markers Genetic Polymorphism Genetic Variation Genomics Genotype Goals HIV HIV-associated neurocognitive disorder Immunology Individual Inflammation Intervention Lead Link Lopinavir Measures Membrane Transport Proteins Mentors Mentorship Modeling Molecular Profiling Morbidity - disease rate Neuraxis Neurocognitive Nevirapine P-Glycoprotein Pathogenesis Patient Care Patients Penetration Peripheral Pharmaceutical Preparations Pharmacogenomics Plasma Population Prognostic Marker Proteins RNA Regimen Research Research Activity Research Personnel Research Training Resistance Risk Risk Assessment Role Sampling Severities Techniques Testing Toxic effect Training Training Activity Universities Variant Work antiretroviral therapy base brain metabolism career career development case control disorder control drug distribution drug metabolism efavirenz genetic analysis genetic variant improved interest neuroAIDS neurocognitive disorder neurotoxicity novel diagnostics personalized medicine prevent research study response simulation skills therapeutic target tool virology

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to provide advanced training for the career development of Dr. Qing Ma, a clinical pharmacologist, in antiretroviral pharmacogenomics, pharmacokinetics and disease modeling in patients with HIV-associated neurocognitive disorders. Through research training, coursework and independent studies, he will develop collaborative relationship with his mentors and skills to achieve his long- term career goal to become an independent clinical investigator focusing on pharmacogenomics of antiretroviral therapy and neurocognitive disorders. He will be working in a rich environment under successful senior investigators from University at Buffalo (Dr. Gene Morse), Vanderbilt University (Dr. David Haas) and University of Rochester (Dr. Giovanni Schifitto). Specific areas of mentorship and training include pharmacogenomics, genetic analysis and bioinformatics, population pharmacokinetic analysis and disease modeling. This proposal focuses on the genomic impact on antiretroviral pharmacokinetics, response and toxicity in patients with HIV-associated neurocognitive disorders (HAND), one of the most prevalent co- morbidities in treated individuals. To achieve this immediate goal, patient samples and longitudinal data will be used from two well-characterized studies: CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China. The risk for HAND may be related to limited distribution of antiretrovirals into the brain but the specific genetic factors associated with variations in brain exposure are largely unknown. Our central hypothesis is that genetic variants that are associated with antiretroviral pharmacokinetics and neurotoxicity will also be associated with HAND in treated individuals. The specific aims of the proposed research are: 1) to determine the association between antiretroviral pharmacokinetics and neurocognitive function among treated patients from CHARTER and Chinese studies; 2) to identify genes and genetic polymorphisms that are associated with antiretroviral exposure, particularly genes that are linked to drug metabolism and drug distribution into the central nervous system; 3) to identify neurotoxicity and inflammation-associated genes that are linked to neurocognitive abnormalities using gene expression profiling and bioinformatics techniques; 4) to develop a disease progression model that integrates pharmacokinetics and the genetic data generated from aims 1 to 3 to predict HAND development. The identification of genetic markers correlated with antiretroviral pharmacokinetics and neurocognitive function will shed lights on HAND etiology and will provide patients and clinicians a useful tool for intervention and risk assessment on an individualized basis. The proposed training and research activities will provide Dr. Qing Ma a foundation that he can generate competitive grant applications in the final years of the award and advance patient care through personalized medicine.

描述（由申请人提供）：该提案的总体目标是为临床药理学家马清博士在艾滋病毒相关神经认知障碍患者的抗逆转录病毒药物基因组学、药代动力学和疾病建模方面的职业发展提供高级培训。通过研究培训、课程作业和独立研究，他将与导师建立合作关系并提高技能，以实现其长期职业目标，成为一名专注于抗逆转录病毒治疗和神经认知障碍的药物基因组学的独立临床研究者。他将在布法罗大学（Gene Morse 博士）、范德比尔特大学（David Haas 博士）和罗切斯特大学（Giovanni Schifitto 博士）成功的高级研究人员的指导下，在丰富的环境中工作。指导和培训的具体领域包括药物基因组学、遗传分析和生物信息学、群体药代动力学分析和疾病建模。该提案的重点是基因组对艾滋病毒相关神经认知障碍（HAND）患者的抗逆转录病毒药代动力学、反应和毒性的影响，这是治疗个体中最常见的合并症之一。为了实现这一近期目标，将使用两项特征明确的研究的患者样本和纵向数据：中枢神经系统艾滋病毒抗逆转录病毒治疗效果研究（CHARTER）和中国中枢神经系统穿透性抗逆转录病毒治疗预防神经艾滋病的临床试验。 HAND 的风险可能与抗逆转录病毒药物进入大脑的有限分布有关，但与大脑暴露变化相关的特定遗传因素在很大程度上尚不清楚。我们的中心假设是，与抗逆转录病毒药代动力学和神经毒性相关的遗传变异也与治疗个体的 HAND 相关。本研究的具体目的是： 1) 根据 CHARTER 和中国研究确定治疗患者的抗逆转录病毒药代动力学与神经认知功能之间的关联； 2) 鉴定与抗逆转录病毒暴露相关的基因和遗传多态性，特别是与药物代谢和药物分布到中枢神经系统相关的基因； 3) 使用基因表达谱和生物信息学技术识别与神经认知异常相关的神经毒性和炎症相关基因； 4) 开发一个疾病进展模型，整合药代动力学和目标 1 至 3 生成的遗传数据来预测 HAND 的发展。与抗逆转录病毒药代动力学和神经认知功能相关的遗传标记的鉴定将揭示手部疾病的病因学，并将为患者和临床医生提供个体化干预和风险评估的有用工具。拟议的培训和研究活动将为马清博士提供一个基础，使他能够在奖项的最后几年提出有竞争力的资助申请，并通过个性化医疗推进患者护理。