Effects of Aging and Inflammation on Intracellular Nucleoside Reverse Transcriptase Inhibitor Pharmacology in the WIHS Cohort

项目摘要 这项应用建议确定年龄是否推动细胞内药理学的变化，并确定临床 以及通过检验增加的假说来影响年龄-药理学关系的免疫因素 随着衰老发生的细胞活化和炎症会反过来减少细胞内的核(T) 转录酶抑制物(NRTI)、胞内代谢物(IM)和内源核苷酸(EN)浓度 感染艾滋病毒的妇女，导致IM：EN比率降低。 我们的目标是：(1)量化和比较老年人(当前年龄≥60岁)细胞内IM和EN浓度 接受替诺福韦(替诺福韦)和恩曲他滨(≤)治疗的年轻(当前年龄5岁)艾滋病毒感染妇女 登记参加WIHS，以及纵向比较老年人细胞内IM和EN浓度(当前 年龄≥60岁)与年轻人(当前年龄≤45岁)采用相同的方案；(2)确定IL-6和sCD163 血浆浓度和/或衰老细胞的存在与IM：EN的变化有关 比率；以及(3)量化和比较登记的HIV感染妇女的细胞内IM和EN浓度 女性机构间HIV研究同时接受替诺福韦和先前测量的尿液 生物标志物，并比较年龄和方案匹配的女性的IM和EN浓度 毒性VS那些没有毒性的人。 拟议的研究将建立在以前进行的药理学和药物相关毒性研究的基础上。 WIHS，解决有关女性衰老的药理学问题，并提供以下初步数据 R01水平的前瞻性研究，探讨IM：EN比率改变的机制和临床影响 治疗感染艾滋病毒的妇女和男子。

PROJECT ABSTRACT This application proposes to determine if age drives changes in intracellular pharmacology, and identify clinical and immunologic factors that affect the age-pharmacology relationship by testing the hypothesis that increased cellular activation and inflammation that occurs with aging will decrease intracellular nucleos(t)ide reverse transcriptase inhibitor (NRTI) intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations in HIV-infected women, resulting in a decreased IM:EN ratio. We aim to: (1) quantify and compare intracellular IM and EN concentrations in older (current age ≥60 years) vs. younger (current age ≤5 years) HIV-infected women receiving tenofovir (TFV) and emtricitabine (FTC) enrolled in the WIHS, as well as compare intracellular IM and EN concentrations longitudinally in older (current age ≥60 years) vs. younger (current age ≤45years) on the same regimen; (2) determine if IL-6 and sCD163 concentrations in plasma and/or the presence of senescent cells are associated with changes in the IM:EN ratio; and (3) quantify and compare intracellular IM and EN concentrations in HIV-infected women enrolled in the Women's Interagency HIV Study receiving tenofovir concurrently with previously measured urinary biomarkers, and compare IM and EN concentrations in age- and regimen-matched women who experienced toxicity vs. those who did not. The proposed study will build off the previous pharmacology and drug-related toxicity research conducted in the WIHS, address questions about the pharmacology of aging in women, and provide preliminary data for R01-level prospective investigations into the mechanism and clinical ramifications of altered IM:EN ratios in treated HIV-infected women and men.