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Antiretroviral-Induced Defects in Muscle Protein Synthesis

抗逆转录病毒引起的肌肉蛋白质合成缺陷

基本信息

批准号：
8006692
负责人：
CHARLES H. LANG
金额：
$ 1.58万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-31 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8006692
关键词：
Address Amino Acids Anti-Retroviral Agents Binding Biochemical Biological Assay Biological Models Branched-Chain Amino Acids Cellular Stress Complex Data Defect Elements Elongation Factor Equilibrium Eukaryotic Initiation Factors Family Genetic Translation Glycoproteins Goals HIV Protease Inhibitors HIV-1 HIV-1 protease Human In Vitro Incubated Indinavir Individual Lamivudine Leucine Lipids Lopinavir Lopinavir/Ritonavir Maintenance Mediating Metabolic Methods Monomeric GTP-Binding Proteins Muscle Muscle Cells Muscle Proteins Myopathy Nucleosides Nutrient Nutritional Peptide Elongation Factor 2 Peptides Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Protease Inhibitor Protein Biosynthesis Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Protein Synthesis Inhibition Proteins Raptors Rattus Regulation Relative (related person)Research Research Personnel Reverse Transcriptase Inhibitors Role Signal Pathway Signal Transduction Skeletal Muscle Small Interfering RNA Staging Stimulus System Testing Translation Initiation Translations Treatment Protocols Tumor Suppressor Proteins Work Zidovudine base carbohydrate metabolism cell growth equilibration disorder in vitro Model in vivo inhibitor/antagonist mTOR protein non-nucleoside reverse transcriptase inhibitors programs response

项目摘要

DESCRIPTION (provided by applicant): HIV-1 protease inhibitors in general have a number of known effects on lipid and carbohydrate metabolism. Our data using both in vivo and in vitro model systems indicate that both indinavir and lopinavir also markedly decrease protein synthesis in skeletal muscle by impairing multiple steps in the control of mRNA translation. The long-term goal of this project is to elucidate the mechanisms by which lopinavir produces myopathy by altering muscle protein balance. The working hypothesis to be tested by the proposed research is that lopinavir antagonizes cell growth signaling systems, that include both eukaryotic initiation factor (elF) 4F and elF2/2B, under both basal conditions and in response to selected anabolic stimuli. Thus, lopinavir alters protein balance by impairing cap-dependent translational control and the formation of the 43S pre-initiation complex. Further, lopinavir adversely effects peptide-chain elongation. To address the questions implicit in our hypothesis, the proposed research has the following Specific Aims: (1) Elucidate the mechanism by which lopinavir impairs elF2B activity in skeletal muscle; (2) Determine whether alterations in the mTOR (mammalian target of rapamycin) nutrient signaling complex are responsible for lopinavir-induced alterations in 4E-BP1 phosphorylation; (3) Determine the mechanism by which lopinavir increases eukaryotic elongation factor (eEF)-2 phosphorylation and whether this change impairs peptide-chain elongation per se; (4) Elucidate the mechanism by which lopinavir impairs the normal anabolic response to nutritional signals (e.g., leucine) in muscle; and (5) Identify the biochemical loci mediating the potentiating effect of zidovudine (AZT) and lamivudine (3TC) on the lopinavir-induced decrease in protein synthesis. Complementary studies using both rats and cultured human myocytes will be used to elucidate the mechanism by which skeletal muscle translation efficiency is reduced by lopinavir, thereby leading to a more complete understanding of the metabolic disturbances produced by this HIV protease inhibitor alone and in combination with other antiretroviral agents. Such data is needed to both realize the full potential and avoid possible pitfalls of this drug in the long-term treatment of HIV-infected individuals.

描述（由申请人提供）：HIV-1蛋白酶抑制剂通常对脂质和碳水化合物代谢具有许多已知的作用。我们的数据使用在体内和体外模型系统表明，茚地那韦和洛匹那韦也显着降低蛋白质合成在骨骼肌中的mRNA翻译的控制通过损害多个步骤。该项目的长期目标是阐明洛匹那韦通过改变肌肉蛋白质平衡产生肌病的机制。拟议的研究要测试的工作假设是，洛匹那韦拮抗细胞生长信号传导系统，包括真核起始因子（elF）4F和elF 2/2B，在基础条件下，并在选定的合成代谢刺激。因此，洛匹那韦通过损害帽依赖性翻译控制和43 S前起始复合物的形成来改变蛋白质平衡。此外，洛匹那韦不利地影响肽链延长。为了解决我们的假设中隐含的问题，所提出的研究具有以下具体目的：（1）阐明洛匹那韦损害骨骼肌中eIF 2B活性的机制;（2）确定mTOR的改变是否与骨骼肌中eIF 2B的活性有关。（雷帕霉素的哺乳动物靶标）营养信号传导复合物负责洛匹那韦诱导的4 E-BP 1磷酸化的改变;（3）确定洛匹那韦增加真核延伸因子（eEF）-2磷酸化的机制，以及这种变化是否损害肽链延伸本身;（4）阐明洛匹那韦损害对营养信号的正常合成代谢反应的机制（例如，亮氨酸）;（5）确定介导齐多夫定（AZT）和拉米夫定（3 TC）对洛匹那韦诱导的蛋白质合成减少的增强作用的生化位点。使用大鼠和培养的人肌细胞的补充研究将用于阐明洛匹那韦降低骨骼肌翻译效率的机制，从而更全面地了解这种HIV蛋白酶抑制剂单独和与其他抗逆转录病毒药物联合产生的代谢紊乱。需要这些数据来充分发挥这种药物在长期治疗艾滋病毒感染者方面的潜力并避免可能的陷阱。