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: 7841367
• 负责人: CHARLES H. LANG
• 金额: $ 44.35万
• 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/7841367
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse effects; Animals; Carbohydrates; Cell Culture System; Chemistry; Complex; Control Animal; Data; Defect; Deoxyglucose; Deposition; Energy Intake; Energy Metabolism; Environment; Equation; Equilibrium; Exhibits; Fatty acid glycerol esters; Funding; Glucose; Glucose Intolerance; Goals; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-1 protease; Health Personnel; Hepatic; Highly Active Antiretroviral Therapy; Hypertension; Inbred F344 Rats; Indinavir; Individual; Infection; Insulin; Insulin Resistance; Investigation; Liver; Lopinavir; Mediating; Metabolic; Metabolic syndrome; Modeling; Molecular; Morbidity - disease rate; Muscle; Muscle Proteins; Muscular Atrophy; Myopathy; Oral Administration; Organ; Parents; Pathogenesis; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Productivity; Protease Inhibitor; Protein Biosynthesis; Proteins; Rattus; Recovery; Reporting; Request for Applications; Research; Research Proposals; Series; Side; Signal Transduction Pathway; Skeletal Muscle; System; Time; Tissues; Toxic effect; Tracer; Training; Transgenic Organisms; Triglycerides; Ubiquitin; Unemployment; United States National Institutes of Health; Viral; Viral Proteins; Virus; Visceral; basal insulin; base; clinically relevant; design; experience; glucose metabolism; glucose production; high school; human FRAP1 protein; in vivo; insight; mortality; multicatalytic endopeptidase complex; novel; parent grant; patient population; preclinical study; protein degradation; protein expression; protein metabolism; protein protein interaction; public health relevance; research study; response; subcutaneous; teacher; wasting

DESCRIPTION (provided by applicant): This application is submitted in response to notice NOT-OD-09-058 (NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) and requests a competitive supplement under ARRA 2009. Our parent grant has provided mechanism insight regarding the decrease in skeletal muscle protein synthesis produced by HIV-1 protease inhibitors such as indinavir and lopinavir (LPV). The long-term goal of the parent grant is to elucidate mechanisms by which LPV and other protease inhibitors produce muscle myopathy. While conducting the studies described in the parent application, we reported HIV-1 transgenic (Tg) rats, which are noninfectious and constitutively express 7 of 9 viral envelop proteins, exhibit muscle atrophy not attributable to decreased caloric intake or increased energy expenditure. We have now administered LPV to HIV-1 Tg rats for 3 months and the observed wasting was markedly greater than that seen in HIV-1 Tg rats without LPV. Furthermore, we have evidence that the co-existence of LPV and HIV-1 viral protein expression decreases muscle protein synthesis in the basal post-absorptive state. Finally, we also noted a marked glucose intolerance, insulin resistance and ectopic deposition of triglycerides in skeletal muscle of HIV-1 Tg rats administered LPV. Hence, it is clear there is a strong interaction between one or more the viral proteins (not the HIV-1 virus per se) and the protease inhibitor which produces a dramatic metabolic phenotype. It seems likely that examining the in vivo effects of protease inhibitors and other HAART drugs in the HIV-1 Tg rat provides a more clinically relevant model because of the drug-viral protein interaction. Therefore, the goal of this competing revision is to determine the mechanism by which the administration of LPV to HIV-1 Tg rats produces this complex metabolic phenotype - with the primary focus being on the changes in glucose and protein metabolism in muscle. Although related, such studies are beyond the direct scope of the parent grant. However, our provocative data warrant further investigation, and the proposed studies can be completed within a 2-yr period. This competing revision requests funds for four specific purposes: 1) Hiring an identified unemployed postdoctoral fellow; 2) employing a high school chemistry teacher as a summer intern; 3) purchase of HIV-1 Tg rats which are extremely expensive; and 4) purchase of supplies necessary for the fellow and intern to have a productive training environment and to successfully complete the designated studies within 2 years. Because the proposed studies were not part of the parent application sufficient unobligated funds are not available. We have been extremely productive during the initial years of the parent application, and the funds supplied in this competing revision will greatly accelerate our research in identifying the cellular and molecular basis for muscle atrophy and insulin resistance produced by protease inhibitors in HIV-infected individuals. PUBLIC HEALTH RELEVANCE: Muscle wasting and insulin resistance in those patients infected with HIV-1 often occur independent of AIDS and may be a direct result of the treatment of these individuals with HIV protease inhibitor drugs. Our studies using HIV-1 transgenic rats administered the commonly prescribed protease inhibitor lopinavir are designed to elucidate the mechanisms by which this class of drugs negatively impacts translational efficiency and insulin action in muscle. Such data are needed to both realize the full potential and avoid possible pitfalls of this drug class in long-term treatment of HIV infection.

DESCRIPTION (provided by applicant): This application is submitted in response to notice NOT-OD-09-058 (NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) and requests a competitive supplement under ARRA 2009. Our parent grant has provided mechanism insight regarding the decrease in skeletal muscle protein synthesis produced by HIV-1 protease inhibitors such as indinavir and lopinavir (LPV).父母赠款的长期目标是阐明LPV和其他蛋白酶抑制剂产生肌肉肌病的机制。在进行父母应用中描述的研究时，我们报道了HIV-1转基因（TG）大鼠，这些大鼠是非感染性和组成型表达9种病毒膜蛋白中的7个，表现出肌肉的萎缩，这不归因于降低热量摄入量或能量消耗。现在，我们已将LPV施用到HIV-1 TG大鼠3个月，观察到的浪费明显大于没有LPV的HIV-1 TG大鼠。此外，我们有证据表明，LPV和HIV-1病毒蛋白表达的共存降低了基础吸收后状态中的肌肉蛋白质合成。最后，我们还注意到甘油三酸酯在HIV-1 TG大鼠骨骼肌中的明显葡萄糖不耐症，胰岛素抵抗和异位沉积。因此，很明显，一种或多种病毒蛋白（不是HIV-1病毒本身）与产生戏剧性代谢表型的蛋白酶抑制剂之间存在很强的相互作用。由于药物患者的蛋白质相互作用，研究蛋白酶抑制剂和其他HAART药物在HIV-1 TG大鼠中的体内作用似乎很可能提供了更相关的模型。因此，这种竞争性修订的目的是确定LPV对HIV -1 TG大鼠的施用产生这种复杂的代谢表型的机制 - 主要重点是肌肉中葡萄糖和蛋白质代谢的变化。尽管相关，但此类研究超出了父母赠款的直接范围。但是，我们的挑衅性数据需要进一步调查，拟议的研究可以在2年内完成。该竞争性修订要求为四个具体目的要求资金：1）雇用已确定的失业博士后研究员； 2）雇用一名高中化学老师作为暑期实习生； 3）购买非常昂贵的HIV-1 TG大鼠； 4）购买同胞和实习生所需的供应量，以拥有富有成效的培训环境，并在2年内成功完成指定的研究。因为拟议的研究不是父母申请的一部分，因此没有足够的未覆盖资金。在父母应用的最初几年中，我们的生产力非常高，并且在此竞争性修订中提供的资金将极大地加速我们的研究，以识别肌肉萎缩和蛋白酶抑制剂在HIV感染的个体中产生的肌肉萎缩和胰岛素抵抗的细胞和分子基础。 公共卫生相关性：感染HIV-1的患者的肌肉浪费和胰岛素抵抗通常是独立于艾滋病的，这可能是治疗这些HIV蛋白酶抑制剂药物的直接结果。我们使用施用通常处方的蛋白酶抑制剂lopinavir的HIV-1转基因大鼠的研究旨在阐明该类别的药物对肌肉中的转化效率和胰岛素作用产生负面影响的机制。需要此类数据以既具有全部潜力，又避免在长期治疗HIV感染中这种药物类别的陷阱。