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）：该提案的总体目的是为抗逆转录病毒药物基因组学，药代动力学和疾病建模的临床药理学士MA博士提供先进的培训。通过研究培训，课程和独立研究，他将与导师和技能建立合作关系，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疾病的独立临床研究者。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）的大学（Gene Morse博士）（Gene Morse博士）（Gene Morse博士）（Gene Morse博士）（Gene Morse博士）（Giovanni Schifitto博士）下工作。指导和培训的特定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。该提案的重点是对艾滋病毒相关神经认知疾病（HAND）患者的抗逆转录病毒药代动力学，反应和毒性的基因组影响，这是治疗个体中最普遍的病态之一。为了实现这一直接目标，将从两项良好的研究中使用患者样本和纵向数据：CNS HIV抗逆转录病毒疗法效应研究（章程）和中枢神经系统穿透性ART的临床试验，以防止中国的神经助剂。手的风险可能与抗逆转录病毒在大脑中的有限分布有关，但是与大脑暴露变化相关的特定遗传因素在很大程度上未知。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将与治疗个体的手相关。拟议的研究的具体目的是：1）确定宪章和中国研究中治疗的患者中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有关的基因和遗传多态性，尤其是与药物代谢和药物分布与中枢神经系统相关的基因； 3）使用基因表达分析和生物信息学技术鉴定与神经认知异常有关的神经毒性和炎症相关基因； 4）开发一个疾病进展模型，该模型整合了药代动力学和目标1至3产生的遗传数据，以预测手部发育。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志物的鉴定将使患者和临床医生在个性化的基础上为患者和临床医生提供一种有用的工具。拟议的培训和研究活动将为Qing博士提供一个基金会，他可以在奖励的最后几年生成竞争性的赠款申请，并通过个性化医学提高患者护理。