AntiretroviraI induced Defects in Muscle Protein Synthes

抗逆转录病毒引起的肌肉蛋白质合成缺陷

• 批准号: 7119423
• 负责人: CHARLES H. LANG
• 金额: $ 29.3万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-20 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119423
• 关键词: drug adverse effect; indinavir; laboratory rat; lamivudine; lopinavir; mTOR protein; muscle disorders; muscle metabolism; muscle proteins; pathologic process; phosphorylation; protein biosynthesis; striated muscles; transcription factor; zidovudine

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有许多已知影响。我们使用体内和体外模型系统都使用的数据表明，indinavir和lopinavir均通过控制mRNA翻译的多个步骤，从而显着降低了骨骼肌中蛋白质的合成。该项目的长期目标是阐明lopinavir通过改变肌肉蛋白质平衡而产生肌病的机制。拟议的研究要检验的工作假设是，在基础条件下，洛匹那韦拮抗细胞生长信号系统，包括真核起始因子（ELF）4F和ELF2/2B，并响应选择的合成代谢刺激。因此，lopinavir通过损害帽依赖性的翻译控制和43S发射络合物的形成来改变蛋白质的平衡。此外，lopinavir不利影响肽链伸长。为了解决我们假设中隐含的问题，拟议的研究具有以下特定目的：（1）阐明lopinavir损害骨骼肌中ELF2B活性的机制； （2）确定MTOR（雷帕霉素的哺乳动物靶标）营养信号传导复合物的改变是否导致lopinavir诱导的4E-BP1磷酸化的改变； （3）确定lopinavir增加真核伸长因子（EEF）-2磷酸化的机制，以及这种变化是否会损害肽链伸长本身； （4）阐明lopinavir损害肌肉中对营养信号（例如亮氨酸）正常合成代谢反应的机制； （5）确定介导Zidovudine（AZT）和Lamivudine（3TC）对lopinavir诱导的蛋白质合成降低的生化基因座的增强作用。使用大鼠和培养的人肌细胞的互补研究将用于阐明lopinavir降低骨骼肌翻译效率的机制，从而使单独的HIV蛋白酶抑制剂和与其他抗雷毒病毒剂组合产生的代谢障碍更加完整地了解。需要此类数据以既具有全部潜力，又避免了这种药物在对HIV感染的个体的长期治疗中的可能陷阱。