HIV Nucleoside Analogs Translational Studies: Resistance and Metabolism

描述（由候选人提供）：本提案概述了一项为期5年的培训计划，使候选人成为一名独立的基于实验室的临床研究者，研究重点是核苷类似物的细胞内代谢与耐药性和临床毒性的关系。候选人已完成儿科住院医师培训和传染病研究金培训。 候选人的目标是通过整合艾滋病毒逆转录酶抑制剂的细胞药理学研究来开发病毒学和药理学的命令在不同个体中的毒性，目的是优化艾滋病毒治疗方案在个体和群体水平，以及结构化的课程，以提高这些领域的科学知识。著名的癌症和病毒药理学家Y.C. Cheng博士将指导候选人的科学发展，与合作导师和具有不同和多学科背景的成功临床和科学研究人员组成的咨询委员会一起。 候选人的研究目标是：i）确定影响细胞内NRTI-三磷酸浓度的宿主因素，以及ii）确定细胞内NRTI-三磷酸浓度对观察到的临床毒性发展的贡献。具体目标1是确定宿主因素对人PBMC中核苷类似物代谢的影响。在具体目标2中，将使用最先进的ELISA技术研究这些核苷磷酸化的个体差异。 将使用HPLC作为金标准评估ELISA的灵敏度。具体目标3是确定细胞内三磷酸盐浓度、线粒体！DNA浓度，以及在接受NRTI方案的HIV感染者中临床或实验室毒性的发展。 上述研究的预期结果将影响HIV治疗的优化，并为核苷类似物使用相关的临床毒性机制提供信息。相对于目前的HPLC方法，ELISA的新奇在于克服灵敏度的缺乏和劳动密集的性质。这将为PK-PD研究提供一种快速和快速的技术，使其有可能筛选大规模人群，其次，有可能用于HIV-1患者的治疗药物监测和个体治疗的优化，特别是在具有严重临床毒性的治疗经验的人中。

DESCRIPTION (provided by candidate): This proposal outlines a 5-year training program for the candidate to become an independent laboratory-based clinical investigator with research focus on intracellular metabolism of nucleoside analogs in relation to resistance and clinical toxicity. The candidate has completed residency training in Pediatrics and fellowship training in Infectious Diseases. The candidate's goal is to develop a command of virology and pharmacology by the integration of research studies on the cellular pharmacology of HIV reverse transcriptase inhibitors in relation to toxicity in different individuals with the aim of optimizing HIV therapeutic regimens both at the individual and population levels, and a structured curriculum to enhance scientific knowledge in these fields. Dr. Y.C Cheng a renowned cancer and viral pharmacologist will mentor the candidate's scientific development together with co-mentors and an advisory committee of accomplished clinical and scientific investigators with diverse and multidisciplinary backgrounds. The candidate's research objectives are to; i) determine host factors that affect the intracellular NRTI-triphosphate concentration, and ii) determine the contribution of the intracellular NRTI-triphosphate concentration to the development of observed clinical toxicities. Specific aim 1 is to determine the effect of host factors on the metabolism of nucleoside analogs in human PBMCs. In specific aim 2 the individual differences in phosphorylation of these nucleosides will be studied using state-of-the-art ELISA technique. The sensitivity of the ELISA will be assessed using HPLC as gold standard. Specific aim 3 is to determine the association among intracellular triphosphate concentration, mitochondria! DNA concentration, and development of clinical or laboratory toxicity in HIV-infected individuals on NRTI-based regimens. The anticipated results from above studies will impact on optimization of HIV therapeutics and inform on the mechanisms of clinical toxicities associated with nucleoside analog usage. The novelty of the ELISA is to overcome, with respect to current HPLC methods, lack of sensitivity and the labor intensive nature. This will provide a quick and rapid technique for PK-PD studies to make it possible to screen large populations, and secondly, has a potential for therapeutic drug monitoring of HIV-1 patients and optimization of individual therapy especially in persons who are heavily treatment-experience with clinical toxicities.