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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（AK 2）是通过腺嘌呤核苷酸的相互转换来调节细胞内稳态的关键调节剂 ATP、ADP和AMP。我们最近证明AK 2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）在细胞和组织中是HIV感染的假定位点。TFV是一种核苷酸反向作为替诺福韦酯前体药物与其他药物联合处方的转录酶抑制剂，治疗艾滋病毒。TFV需要两个连续的磷酸化步骤，以成为一个磷酸化酶。活跃替诺福韦酯也是FDA唯一批准的HIV暴露前预防（PrEP）的组成部分方案. AK 2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，约1200个个体，并确定可能影响TFV激活的AK 2遗传变异。到目前为止，体外研究已经表明，其中几种变体确实影响AK 2对TFV的活性。在前进的过程中，将具体测试老化对AK 2表达和活性的影响。确定TFV的活性- 激活激酶，特别是AK 2，在老年人和年轻人中表现出不同的活性，由于老年人（≥50岁）约占每年新感染艾滋病毒人数的17%，因此这一点非常重要。该建议的目的是：1）测量单个细胞中TFV和TFV磷酸化代谢物的水平，循环中的CD 4 + T细胞是HIV感染的关键靶点，并确定药物/代谢物水平老年人（65-80岁）和年轻人（18-30岁）之间的差异; 2）测试模式的假设，激活TFV的激酶的表达在老年人（65-80岁）与年轻人（65-80岁）中是不同的。 18-30）在循环CD 4 + T细胞中的表达。