Antiretroviral pharmacogenomics, pharmacokinetics and toxicity in neuroAIDS

描述(由申请人提供)： 这项建议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，内容涉及HIV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。通过研究培训、课程学习和独立研究，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员。他将在一个丰富的环境中工作，在来自布法罗大学(吉恩·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·施菲托博士)的成功高级调查人员的指导下工作。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、人群药代动力学分析和疾病建模。这项建议侧重于基因组对HIV相关神经认知障碍(HAND)患者抗逆转录病毒药物动力学、反应和毒性的影响，HAND是接受治疗的个体中最常见的共病之一。为了实现这一近期目标，中国的患者样本和纵向数据将来自两项很有特色的研究：CNS HIV抗逆转录病毒治疗效果研究(CHECURE)和CNS穿透性ART预防神经艾滋病的临床试验。手的风险可能与抗逆转录病毒药物在大脑中的有限分布有关，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基因变异也将与接受治疗的个体的Hand相关。这项拟议研究的具体目的是：1)确定CHETER和CHIENT研究中接受抗逆转录病毒治疗的患者的药物动力学和神经认知功能之间的关系；2)确定与抗逆转录病毒暴露相关的基因和基因多态性，尤其是与药物代谢和药物进入中枢神经系统有关的基因；3)利用基因表达谱和生物信息学技术确定与神经认知异常有关的神经毒性和炎症相关基因；4)建立整合药物动力学和目标1至3产生的遗传数据来预测手部发育的疾病进展模型。识别与抗逆转录病毒药物动力学和神经认知功能相关的遗传标记将有助于揭示手部病因学，并将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青博士提供一个基础，使他能够在奖项的最后几年产生有竞争力的拨款申请，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.