Protein Nutrition in Experimental Uremia
实验性尿毒症中的蛋白质营养
基本信息
- 批准号:8004337
- 负责人:
- 金额:$ 10万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-01-26 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseChronic Kidney FailureComplexDegradation PathwayDown-RegulationEnzymesExhibitsExperimental ModelsGlucocorticoidsGoalsGrantInsulinInsulin ReceptorInsulin-Like Growth Factor IInsulin-Like-Growth Factor I ReceptorKidney FailureMediatingMetabolic acidosisMetabolismModelingMorbidity - disease rateMusMuscleMuscle CellsMuscle ProteinsMuscular AtrophyMyofibrilsPTEN genePathway interactionsPhysiologicalProcessProteinsProteolysisRoleSignal PathwaySignal TransductionStructureSystemTestingTransgenic MiceUbiquitinUremiabasecaspase-3combatin vivoinsulin receptor substrate 1 proteinmortalitymulticatalytic endopeptidase complexmuscle formmuscular structurenovelnutritionpreventprotein degradationreceptorresponsewasting
项目摘要
Abnormalities in metabolism leading to loss of muscle mass contribute to the morbidity and mortality of
kidney failure. Our long-term goal is to identify uremia-induced mechanisms causing muscle loss in order to
devise novel therapies to combat this problem. We have identified new processes that cause muscle protein
losses: 1) caspase-3 activation is the initial step that breaks down the complex structure of muscle yielding
substrates that are degraded by the ubiquitin system. 2) The trigger that accelerated muscle loss is
decreased activity of IRS-1 associated phosphatidylinositol 3-kinase activity (IRS-1-PI3K). Decreased IRS-1-
PI3K stimulates caspase-3 and the ubiquitin system, including the critical enzyme, atrogin-1/MAFbx. 3)
Physiological levels of glucocorticoids (GC) are absolutely required to activate protein degradation pathways.
Thus, we propose a "two hit" process: GC and suppressed insulin responses synergistically suppress IRS-1-
PI3K activity and initiate muscle proteolysis. We will test the two hit model using experimental models; mice
lacking the insulin or IGF-1 receptor in muscle. We will extend our study to uremia using transgenic mice
that exhibit activation of the IRS-1-PI3K pathway (e.g., PTEN deletion, Akt or IGF-1). Specifically, we will: 1)
test if there is an essential role for both GC and impaired insulin/IGF-1 responses that stimulates muscle
proteolysis in mice with deficiency of the insulin or the IGF-1 receptor or both receptors but only in muscle; 2)
examine the mechanism for GC- and insulin/IGF-1 deficiency-dependent downregulation of IRS-1-PI3K
activity in muscle; and 3) examine how manipulation of PI3K and Akt activities in vivo will change uremia-
induced muscle proteolysis using transgenic mice. The significance of our results is that the two-hit model
could apply to many conditions because GC and decreased insulin responses are present in many catabolic
illnesses,
代谢紊乱导致肌肉质量损失,导致
肾衰竭我们的长期目标是确定尿毒症引起的肌肉损失的机制,
设计新的疗法来解决这个问题。我们已经发现了导致肌肉蛋白质
损失:1)半胱天冬酶-3激活是打破肌肉屈服的复杂结构的初始步骤。
底物被泛素系统降解。2)加速肌肉萎缩的诱因是
IRS-1相关磷脂酰肌醇3-激酶活性(IRS-1-PI 3 K)降低。降低IRS-1-
PI 3 K刺激caspase-3和泛素系统,包括关键酶atrogin-1/MAFbx。第三章
生理水平的糖皮质激素(GC)是激活蛋白质降解途径所必需的。
因此,我们提出了一个“两次打击”的过程:GC和抑制胰岛素反应协同抑制IRS-1,
PI 3 K活性和启动肌肉蛋白水解。我们将使用实验模型来测试两次打击模型;小鼠
肌肉中缺乏胰岛素或IGF-1受体。我们将使用转基因小鼠将我们的研究扩展到尿毒症
表现出IRS-1-PI 3 K途径的激活(例如,PTEN缺失、Akt或IGF-1)。具体而言,我们将:1)
测试GC和受损的胰岛素/IGF-1反应是否在刺激肌肉中起重要作用
在胰岛素或IGF-1受体或两种受体缺乏但仅在肌肉中的小鼠中的蛋白水解; 2)
检查IRS-1-PI 3 K的GC和胰岛素/IGF-1缺陷依赖性下调的机制
肌肉中的活性;以及3)检查体内PI 3 K和Akt活性的操纵将如何改变尿毒症。
使用转基因小鼠诱导肌肉蛋白水解。我们结果的重要性在于两击模型
可以应用于许多条件,因为GC和胰岛素反应降低存在于许多分解代谢中,
疾病,
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WILLIAM Evans MITCH其他文献
WILLIAM Evans MITCH的其他文献
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{{ truncateString('WILLIAM Evans MITCH', 18)}}的其他基金
SMAD SIGNALING IN ANGIOTENSIN II-MEDIATED RENAL FIBROSIS
血管紧张素 II 介导的肾纤维化中的 SMAD 信号传导
- 批准号:
7061191 - 财政年份:2005
- 资助金额:
$ 10万 - 项目类别:
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Research Units