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REGULATION OF PROTEIN TURNOVER IN SEPSIS

脓毒症中蛋白质周转的调节

基本信息

批准号：
7904745
负责人：
Scot R Kimball
金额：
$ 24.69万
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：
1989
资助国家：
美国
起止时间：
1989-07-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904745
关键词：
Ablation Acute Affect Agar Amino Acids Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Biochemical Chronic Complex Data Defect Electroporation Funding Gastrocnemius Muscle Genetic Genetic Translation Glycogen Synthase Kinases Goals Grant Hormones Impairment Incubated Inflammation Inflammatory Knockout Mice Laboratories Leucine Mediating Metabolic Morbidity - disease rate Muscle Muscle Proteins Norleucine Nutrient Nutritional Pathway interactions Peptide Initiation Factors Phase Phosphorylation Plasma Plasmids Process Protein Biosynthesis Protein Kinase Protein Synthesis Inhibition Protein-Serine-Threonine Kinases Proteins Rattus Recovery Regulation Relative (related person)Reporting Research Research Personnel Role Sepsis Signal Pathway Signal Transduction Signal Transduction Pathway Sirolimus Skeletal Muscle Sterility Testing Therapeutic Transgenic Organisms Translation Initiation Uncertainty Variant analog base branched-chain-amino-acid transaminase dietary supplements implantation in vivo inhibitor/antagonist mTOR protein mortality muscle form overexpression prevent programs promoter protein degradation response restraint septic skeletal muscle wasting

项目摘要

DESCRIPTION (provided by applicant): The objective of the studies described herein are directed at developing strategies for enhancing muscle mass through understanding the biochemical basis for the impairment in protein synthesis that characterizes the metabolic response to sepsis. Sustained skeletal muscle wasting contributes to the morbidity and mortality associated with sepsis. We established that sepsis, but not sterile inflammation, induces specific maladjustments in at least two cell signaling pathways culminating in the inhibition of protein synthesis by limiting the process of mRNA translation initiation in skeletal muscle. One includes the mammalian target of rapamycin (mTOR), a serine/threonine kinase that controls phosphorylation of two other protein factors S6K1 and 4E-BP1 that regulate mRNA translation and formation of an active elF4E-elF4G complex and elF4G phosphorylation. The second is the phosphorylation of elF2Be through activation of glycogen synthase kinase-3p (GSKSfi). The following specific aims use transgenic, pharmacologic and/or nutritional approaches to validate the relative contribution and potential therapeutic relevance of these signaling pathways in the restraint in protein synthesis, and hence skeletal muscle protein, to a septic insult. Specific Aim 1 will investigate the contribution of lowered mTOR activity to the decrease in skeletal muscle protein synthesis and the ability of leucine (or norleucine) to reverse that inhibition of mTOR and elF4G phopshorylation during sepsis. We will also determine if stimulating mTOR activity with nutrients reverses the sepsis-induced inhibition of skeletal muscle protein synthesis and the role of pharacolgical inhibition and genetic ablation of mTOR in nutrient stimulated protein synthesis. Access to the BCAT2 knockout mouse will allow us to establish whether leucine or a leucine metabolite is responsible for leucine's activation of mTOR signaling. Specific Aim 2 will investigate the impact of reversing the septic-induced increase in phosphorylation and decrease in cellular content of elF2Be using genetically-dependent anti-inflammatory therapy, pharmacological inhibition of GSK-3(3 and over expression of non-phosphorylatable elF2Be on muscle protein synthesis during sepsis. We will test the hypothesis that treatment of muscles from septic rats with the GSK3P inhibitors LiCI, SB216763 and SB415286 or expression of active, non-phosphorylatable elF2Be will abrogate the sepsis-induced inhibition of protein synthesis in skeletal muscle.

描述（由申请人提供）：本文所述研究的目的是通过理解表征脓毒症代谢反应的蛋白质合成受损的生物化学基础来开发增强肌肉质量的策略。持续的骨骼肌萎缩导致脓毒症相关的发病率和死亡率。我们确定，脓毒症，但不是无菌炎症，诱导特定失调，在至少两个细胞信号通路最终抑制蛋白质合成的限制过程中的mRNA翻译启动骨骼肌。一种包括雷帕霉素的哺乳动物靶标（mTOR），其是一种丝氨酸/苏氨酸激酶，其控制另外两种蛋白质因子S6 K1和4 E-BP 1的磷酸化，所述蛋白质因子S6 K1和4 E-BP 1调节mRNA翻译和活性eIF 4 E-eIF 4G复合物的形成以及eIF 4G磷酸化。第二种是通过激活糖原合成酶激酶-3 β（GSKSfi）使eIF 2Be磷酸化。以下具体目的使用转基因、药理学和/或营养方法来验证这些信号传导途径在蛋白质合成以及因此骨骼肌蛋白对脓毒性损伤的抑制中的相对贡献和潜在治疗相关性。具体目标1将研究降低的mTOR活性对骨骼肌蛋白质合成减少的贡献以及亮氨酸（或正亮氨酸）逆转脓毒症期间mTOR和eIF 4G磷酸化的抑制的能力。我们还将确定用营养物刺激mTOR活性是否逆转脓毒症诱导的骨骼肌蛋白质合成抑制以及mTOR的药理学抑制和遗传消融在营养物刺激的蛋白质合成中的作用。获得BCAT 2敲除小鼠将使我们能够确定亮氨酸或亮氨酸代谢物是否负责亮氨酸激活mTOR信号传导。具体目标2将研究使用遗传依赖性抗炎治疗、GSK-3 β的药理学抑制和不可磷酸化eIF 2Be的过度表达逆转败血症诱导的eIF 2Be磷酸化增加和细胞含量减少对败血症期间肌肉蛋白质合成的影响。我们将检验以下假设：用GSK 3 β抑制剂LiCl、SB 216763和SB 415286或活性的、不可磷酸化的eIF 2Be的表达处理来自脓毒症大鼠的肌肉将消除脓毒症诱导的骨骼肌中蛋白质合成的抑制。