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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该应用旨在确定年龄是否会驱动细胞内药理学的变化，并确定临床和影响年龄-药理学关系的免疫因素，通过检验增加的假设随着衰老而发生的细胞活化和炎症将减少细胞内核苷（酸）逆转转录酶抑制剂 (NRTI) 细胞内代谢物 (IM) 和内源核苷酸 (EN) 浓度感染 HIV 的女性，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）的细胞内 IM 和 EN 浓度与接受替诺福韦 (TFV) 和恩曲他滨 (FTC) 治疗的年轻（当前年龄 ≤ 5 岁）HIV 感染女性相比参加 WIHS，并纵向比较老年人（当前）的细胞内 IM 和 EN 浓度年龄 ≥ 60 岁）与较年轻的人（当前年龄 ≤ 45 岁）采用相同的治疗方案；(2) 确定 IL-6 和 sCD163 是否有效血浆中的浓度和/或衰老细胞的存在与 IM:EN 的变化有关 (3) 量化并比较纳入研究的 HIV 感染女性的细胞内 IM 和 EN 浓度妇女机构间艾滋病毒研究在接受替诺福韦治疗的同时，还进行了之前测量的尿生物标志物，并比较年龄和治疗方案匹配的女性的 IM 和 EN 浓度，这些女性经历过毒性与那些没有毒性的人相比。拟议的研究将建立在先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，并提供初步数据对 IM:EN 比率改变的机制和临床影响的 R01 水平前瞻性研究感染艾滋病毒的女性和接受治疗的男性。