HIV Nucleoside Analogs Translational Studies: Resistance and Metabolism

描述(由候选人提供)：该建议概述了一个为期5年的培训计划，候选人将成为一名独立的实验室临床研究人员，重点研究与耐药性和临床毒性有关的核苷类似物的细胞内代谢。应聘者已完成儿科住院医师培训和传染病研究员培训。 候选人的目标是通过整合关于艾滋病毒逆转录酶抑制剂的细胞药理学与不同个体毒性的研究，以期在个人和人群层面上优化艾滋病毒治疗方案，并制定一项结构化的课程，以增强这些领域的科学知识，从而掌握病毒学和药理学。著名的癌症和病毒药剂学家郑永强博士将与共同导师和一个由具有不同和多学科背景的资深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的发展的贡献。具体目的1是确定宿主因素对核苷类似物在人外周血单核细胞中代谢的影响。在具体目标2中，将使用最先进的酶联免疫吸附试验技术研究这些核苷的磷酸化的个体差异。 以高效液相色谱法为金标准，对该方法的敏感性进行评价。具体目标3是确定细胞内三磷酸浓度、线粒体！NRTI方案中艾滋病毒感染者的DNA浓度和临床或实验室毒性的发展。 上述研究的预期结果将对HIV治疗的优化产生影响，并为与核苷类似物使用相关的临床毒性机制提供信息。该方法的创新之处在于克服了现有高效液相色谱检测方法灵敏度低、劳动强度大的缺点。这将为PK-PD研究提供一种快速和快速的技术，使其能够对大量人群进行筛查；其次，它有可能对HIV-1患者的治疗药物进行监测，并优化个人治疗，特别是在有严重临床毒性治疗经验的人中。

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.