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

WIHS 队列中衰老和炎症对细胞内核苷逆转录酶抑制剂药理学的影响

• 批准号: 9791318
• 负责人: Julie Brumer Dumond
• 金额: $ 13.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791318
• 关键词: Address; Affect; Age; Age-Years; Aging; Anti-Retroviral Agents; Biological Markers; C-reactive protein; CD28 gene; CD4 Lymphocyte Count; CD4/CD8 ratio procedure; CD8-Positive T-Lymphocytes; Cell Aging; Cells; Clinical; Clinical Data; Cohort Studies; Complex; Data; Databases; Detection; Diphosphates; Drug toxicity; Drug usage; Enrollment; Formulation; Glomerular Filtration Rate; Goals; HIV; Hepatitis C; High Risk Woman; Human; Immunologic Factors; Immunologics; In Vitro; Inflammation; Interleukin-6; Intervention; Investigation; Kidney; Macrophage Activation; Measures; Menopause; Modeling; Modernization; Morbidity - disease rate; Nucleosides; Nucleotides; Outcome; Ovarian; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Prospective Studies; Regimen; Renal function; Research; Reverse Transcriptase Inhibitors; Risk; Safety; Sampling; Statistical Models; T-Lymphocyte; Tenofovir; Testing; Time; Toxic effect; Vertebral column; Visit; Woman; Women’s Interagency HIV Study; Work; age effect; age related; antiretroviral therapy; case control; design; emtricitabine; experience; improved; kidney dysfunction; men; monocyte; mullerian-inhibiting hormone; older women; oncology; pharmacodynamic model; pharmacokinetic model; predictive marker; prospective; repository; senescence; urinary

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.

项目摘要 该申请提案以确定年龄是否驱动细胞内药理学的变化并确定临床 以及通过测试增加的假设来影响年龄 - 药理学关系的免疫因素 随着衰老而发生的细胞激活和炎症将降低细胞内核（T）IDE反向 转录酶抑制剂（NRTI）细胞内代谢产物（IM）和内源性核苷（EN）浓度 艾滋病毒感染的妇女，导致IM：EN比率下降。 我们的目标是：（1）量化和比较较老的细胞内IM和EN浓度（当前年龄≥60岁） 与年轻（当前年龄≤5岁）接受Tenofovir（TFV）和Emtricitabine（FTC）的艾滋病毒感染的妇女 在WIHS中注册，并比较细胞内IM和EN浓度在较大的较大的情况下（电流） 年龄≥60岁）与同一方案的年轻（当前年龄≤45岁）； （2）确定IL-6和SCD163是否 血浆中的浓度和/或感觉细胞的存在与IM的变化有关 比率; （3）量化和比较入学的HIV感染妇女中细胞内IM和EN的浓度 妇女的机构间艾滋病毒研究接受替诺福韦并同时接受尿液 生物标志物，并比较经历年龄和方案匹配的妇女的IM和EN浓度 毒性与那些没有的人。 拟议的研究将建立以前的药理学和药物有关的毒性研究 WIHS，解决有关妇女衰老药理学的问题，并提供初步数据 R01级的前瞻性研究对IM：EN比率的机制和临床后果的研究 治疗了艾滋病毒感染的男女。