Antiretroviral pharmacogenomics, pharmacokinetics and toxicity in neuroAIDS

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青博士的职业发展提供高级培训，包括抗逆转录病毒药物基因组学、药代动力学和艾滋病毒相关神经认知障碍患者的疾病建模。通过研究培训，课程和独立学习，他将与他的导师和技能发展合作关系，以实现他的长期职业目标，成为一名独立的临床研究者，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。他将在来自布法罗大学（Gene莫尔斯博士）、范德比尔特大学（大卫·哈斯博士）和罗切斯特大学（乔瓦尼·斯基菲托博士）的成功高级研究人员的带领下，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。该提案重点关注基因组对抗逆转录病毒药代动力学、HIV相关神经认知障碍（HAND）患者的反应和毒性的影响，HAND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，将使用来自两项充分表征的研究的患者样本和纵向数据：CNS HIV抗逆转录病毒治疗效果研究（CHARTER）和CNS穿透性ART预防中国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分布有限有关，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，与抗逆转录病毒药物动力学和神经毒性相关的遗传变异也将与治疗个体的HAND相关。拟开展的研究的具体目的是：1）确定CHARTER研究和中国研究中接受治疗的患者中抗逆转录病毒药代动力学和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鉴定与神经认知异常相关的神经毒性和炎症相关基因; 4）开发整合药代动力学和目标1至3产生的遗传数据的疾病进展模型，以预测HAND发展。识别与抗逆转录病毒药物代谢动力学和神经认知功能相关的遗传标记将揭示HAND病因，并为患者和临床医生提供个性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庆博士提供一个基础，使他能够在该奖项的最后几年提出有竞争力的赠款申请，并通过个性化医疗促进患者护理。

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.