HIV Nucleoside Analogs Translational Studies: Resistance and Metabolism

描述（由候选人提供）：该提案概述了候选人的 5 年培训计划，以成为一名独立的实验室临床研究者，其研究重点是与耐药性和临床毒性相关的核苷类似物的细胞内代谢。候选人已完成儿科住院医师培训和传染病专科培训。 候选人的目标是通过整合与不同个体毒性相关的 HIV 逆转录酶抑制剂的细胞药理学研究，培养对病毒学和药理学的掌握，目的是在个人和群体水平上优化 HIV 治疗方案，并制定结构化课程来增强这些领域的科学知识。著名的癌症和病毒药理学家 Y.C Cheng 博士将与共同导师以及由具有多元化和多学科背景的临床和科学研究人员组成的咨询委员会一起指导候选人的科学发展。 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。 ELISA 的灵敏度将使用 HPLC 作为金标准进行评估。具体目标3是确定细胞内三磷酸浓度与线粒体之间的关联！ HIV 感染者在接受基于 NRTI 的治疗方案时，DNA 浓度以及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，并为与核苷类似物使用相关的临床毒性机制提供信息。 ELISA 的新颖之处在于克服了当前 HPLC 方法缺乏灵敏度和劳动密集型的问题。这将为 PK-PD 研究提供一种快捷的技术，使筛选大量人群成为可能，其次，有可能对 HIV-1 患者进行治疗药物监测并优化个体治疗，特别是对于具有丰富临床毒性治疗经验的患者。

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.