HIV Nucleoside Analogs Translational Studies: Resistance and Metabolism

HIV 核苷类似物转化研究：耐药性和代谢

• 批准号: 7802894
• 负责人: ELIJAH PAINTSIL
• 金额: $ 12.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802894
• 关键词: Adverse effects; Advisory Committees; Affect; Age; Anti-Retroviral Agents; Antiretroviral resistance; Arts; Behavioral; Biological Assay; Bovine Serum Albumin; Cells; Clinical; Clinical Investigator; Communicable Diseases; Conflict (Psychology); Coupled; DNA; Data; Detection; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Monitoring; Drug resistance; Educational Curriculum; Engineering; Enzyme-Linked Immunosorbent Assay; Epidemiology; Etiology; Evolution; Fellowship; Freund' s Adjuvant; Gender; Goals; Gold; HIV; HIV-1; Heterogeneity; High Pressure Liquid Chromatography; Highly Active Antiretroviral Therapy; Human; Immune Sera; Impairment; In Vitro; Individual; Individual Differences; Integration Host Factors; Knowledge; Label; Laboratories; Lamivudine; Lead; Mass Spectrum Analysis; Mentors; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Multi-Drug Resistance; Mutation; Nature; Nucleosides; Oryctolagus cuniculus; Patients; Pediatrics; Persons; Pharmacology; Phosphorylation; Plasma; Population; Process; Regimen; Research; Research Personnel; Residencies; Resistance; Reverse Transcriptase Inhibitors; Role; Site-Directed Mutagenesis; Structure; Techniques; Therapeutic; Therapeutic Uses; Time; Toxic effect; Training; Training Programs; Treatment outcome; Viral; Viral Cancer; Viral Load result; Virus; Work; Zidovudine; analog; antiretroviral therapy; base; clinically relevant; cohort; drug resistant virus; epidemiologic data; experience; fitness; inhibitor/antagonist; innovation; metabolic abnormality assessment; mortality; multidisciplinary; mutant; next generation; novel; nucleoside analog; programs; rapid technique; research study; resistance mutation; response; skills; success; tool; translational study; transmission process; tripolyphosphate; virology

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.

描述（由候选人提供）：该提案概述了候选人成为独立实验室临床研究者的5年培训计划，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。该候选人已完成儿科住院医师培训和传染病研究员培训。