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Drug Phosphorylation and Aging

药物磷酸化与老化

基本信息

批准号：
10613052
负责人：
Benjamin Carl Orsburn
金额：
$ 21.04万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10613052
关键词：
AIDS prevention Adenine Nucleotides Adherence Age Age-Years Aging Amino Acid Sequence Anti-Retroviral Agents Area Biology of Aging CD4 Positive T Lymphocytes Cell Separation Cells Clinical Data Detection Elderly Enzymes Exhibits FDA approved Foundations Fumarates Genomic DNA Goals HIV HIV Infections Heterogeneity Homeostasis Human In Vitro Individual Laboratories Magnetism Mass Spectrum Analysis Measurement Measures Methods Nucleotides Organ Participant Pathway interactions Pattern Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Prodrugs Proteins Proteome Proteomics Regimen Research Resolution Reverse Transcriptase Inhibitors Role Sampling Site Speed Strategic Planning Technology Tenofovir Testing Time Tissue Extracts Tissues Touch sensation United States National Institutes of Health Variant Whole Blood Work adenylate kinase age effect base cell type clinical outcome measures drug action drug disposition enzyme activity genetic variant innovation insight liquid chromatography mass spectrometry pre-exposure prophylaxis protein expression response small molecule time of flight mass spectrometry time use young adult

项目摘要

Adenylate kinase 2 (AK2) is a key regulator of cellular homeostasis via the interconversion of adenine nucleotides ATP, ADP, and AMP. We recently demonstrated that AK2 plays a crucial role in the activation of the antiretroviral drug tenofovir (TFV) in cells and tissues that are putative sites of HIV infection. TFV is a nucleotide reverse transcriptase inhibitor that is prescribed as a tenofovir disoproxil prodrug in combination with other drugs for the treatment of HIV. TFV requires two sequential phosphorylation steps in order to become pharmacologically active. Tenofovir disoproxil is also a component of the only FDA approved HIV pre-exposure prophylaxis (PrEP) regimen. The identification of AK2 as a TFV-activating kinase spurred us to sequence the human genomic DNA of ~1200 individuals and identify AK2 genetic variants that could impact TFV activation. Thus far, in vitro studies have revealed that several of these variants do indeed impact AK2 activity towards TFV. In moving forward, an effect of aging on AK2 expression and activity will be tested specifically. Determining whether the activity of TFV- activating kinases, particularly AK2, could exhibit differential activity in older versus younger adults is of importance since older adults (≥50 years of age) account for an approximate 17% of new HIV infections annually. The aims of this proposal are to: 1) measure the levels of TFV and phosphorylated metabolites of TFV in single circulating CD4+ T cells that are key targets for HIV infection, and determine whether the drug/metabolite levels differ between older adults (ages 65-80) and younger adults (ages 18-30); 2) test the hypothesis that the patterns of expression of kinases that activate TFV are divergent in older adults (ages 65-80) versus younger adults (ages 18-30) in circulating CD4+ T cells using single cell proteomics.

腺苷酸激酶 2 (AK2) 是通过腺嘌呤核苷酸相互转化来调节细胞稳态的关键因子 ATP、ADP 和 AMP。我们最近证明 AK2 在抗逆转录病毒的激活中起着至关重要的作用药物替诺福韦（TFV）存在于假定的 HIV 感染部位的细胞和组织中。 TFV 是核苷酸反向转录酶抑制剂，作为替诺福韦二吡呋酯前药与其他药物联合使用，用于治疗治疗艾滋病毒。 TFV 需要两个连续的磷酸化步骤才能发挥药理学作用积极的。替诺福韦二吡呋酯也是 FDA 唯一批准的 HIV 暴露前预防 (PrEP) 的组成部分养生法。 AK2 作为 TFV 激活激酶的鉴定促使我们对人类基因组 DNA 进行测序对约 1200 名个体进行了研究，并识别出可能影响 TFV 激活的 AK2 遗传变异。迄今为止，体外研究研究表明，其中一些变体确实会影响 AK2 对 TFV 的活性。在前进的过程中，将具体测试衰老对 AK2 表达和活性的影响。确定 TFV- 的活性是否激活激酶，特别是 AK2，在老年人和年轻人中可能表现出不同的活性重要性，因为老年人（≥50 岁）每年约占新发 HIV 感染的 17%。该提案的目的是：1）测量单个样本中 TFV 和 TFV 磷酸化代谢物的水平循环 CD4+ T 细胞是 HIV 感染的关键目标，并确定药物/代谢物水平是否老年人（65-80 岁）和年轻人（18-30 岁）之间存在差异； 2）检验模式的假设激活 TFV 的激酶的表达在老年人（65-80 岁）与年轻人（年龄 18-30) 使用单细胞蛋白质组学研究循环 CD4+ T 细胞。