Glucocorticoid control of gene expression during skeletal muscle atrophy

骨骼肌萎缩过程中糖皮质激素对基因表达的控制

• 批准号: 8012965
• 负责人: Sue C Bodine
• 金额: $ 1.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-28 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012965
• 关键词: Adrenal Glands; Adrenergic Agonists; Adverse effects; Aging; Animal Welfare; Anti-Inflammatory Agents; Anti-inflammatory; Atrophic; Base Pairing; Bibliography; Biological Assay; Cachexia; Cartilage; Cells; Chronic Disease; Clenbuterol; Country; Data; Electroporation; Environment; Environmental Impact; Equipment; Fasting; Fluorescence; Funding; Gene Deletion; Gene Expression; Genes; Glucocorticoid Receptor; Glucocorticoids; Grant; Health; Hormones; Human; Hyperglycemia; IACUC; Immobilization; Inflammatory; Insulin Resistance; Insulin-Like Growth Factor I; International; Laboratories; Life; Ligands; Modeling; Molecular; Mus; Muscle; Muscular Atrophy; Mutation; Nature; Nerve; Paper; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Principal Investigator; Proteins; Publishing; Regulatory Element; Relative (related person); Research; Research Ethics Committees; Research Personnel; Resources; Respiratory physiology; Role; Sepsis; Signal Transduction; Site; Skeletal Muscle; Study Section; Techniques; Transcriptional Activation; Transfection; Up-Regulation; Vertebrates; Work; abstracting; bone; chromatin immunoprecipitation; clinically relevant; expiration; expression vector; gene induction; genetic resource; human subject; interest; material transfer agreement; muscle form; programs; promoter; research study; response; skeletal muscle wasting; success; tool; ubiquitin-protein ligase

Skeletal muscle wasting, or atrophy, is a major human health issue. Immobilization, nerve damage, cachexia, sepsis, and aging all induce significant and possibly even life-threatening losses in skeletal muscle mass to the point of impairing adequate ambulatory or respiratory function. Adrenal glucocorticoid hormones are also potent inducers of skeletal muscle atrophy. Physiological levels of glucocorticoids support muscle atrophy in sepsis, renal failure, and other catabolic conditions. In addition, synthetic glucocorticoids are commonly prescribed as potent anti-inflammatory drugs but prolonged use leads to debilitating hyperglycemia, insulin resistance, and bone, cartilage, and muscle loss. New "selective" glucocorticoid receptor ligands have been described that repress inflammatory gene expression but are less potent at up- regulation of other classes of glucocorticoid responsive genes, thus showing good pharmaceutical potential. However, none have been evaluated for effects on skeletal muscle. Furthermore, no drugs are currently available to directly alleviate or prevent muscle atrophy under any circumstances, including glucocorticoid treatment. Inhibition of glucocorticoid receptor action selectively in skeletal muscle would present an opportunity to alleviate atrophy under a variety of conditions. Indeed, activation of either the IGF-1 or beta2 adrenergic receptors strongly inhibits glucocorticoid induced atrophy. The molecular details of this inhibition are poorly understood, as is whether distinct or overlapping signal transduction pathways are used by each receptor to block glucocortcoid receptor activity. Therefore, we propose to 1) Determine the relative contribution of MuRFt and MAFbx genes to glucocorticoid induced skeletal muscle atrophy, 2) Evaluate recently developed selective anti-inflammatory glucocorticoid receptor ligands for effects on muscle atrophy and MuRF1 and MAFbx gene transcription, and 3) Investigate molecular details of glucocorticoid-induced regulation of the MuRF1 gene, with particular focus on the opposing actions of IGF-1 and beta2 adrenergic agonists. Newly developed genetic resources, pharmacological tools, and molecular techniques are available to accomplish these aims. Thus, this proposal represents an opportunity to apply new concepts and cutting-edge technology regarding glucocorticoid receptor function directly to the highly medically relevant problem of skeletal muscle atrophy.

骨骼肌萎缩或称萎缩是人类的主要健康问题， 问题.固定、神经损伤、恶病质、脓毒症和衰老都诱导显著的和可能的 甚至危及生命的骨骼肌质量损失到损害足够的走动或 呼吸功能肾上腺糖皮质激素也是骨骼肌的强效诱导剂 萎缩生理水平的糖皮质激素支持脓毒症、肾衰竭和 其他代谢条件。此外，合成糖皮质激素通常被处方为有效的 抗炎药，但长期使用会导致衰弱性高血糖症，胰岛素抵抗， 骨骼、软骨和肌肉损失。已经描述了新的“选择性”糖皮质激素受体配体， 抑制炎症基因表达，但在上调其他类型的 糖皮质激素应答基因，因此显示出良好的药学潜力。然而， 评估了对骨骼肌的影响。此外，目前没有药物可直接用于 缓解或预防任何情况下的肌肉萎缩，包括糖皮质激素治疗。 选择性抑制骨骼肌中糖皮质激素受体的作用将提供机会， 缓解各种条件下的萎缩。事实上，IGF-1或β 2肾上腺素能受体的激活 受体强烈抑制糖皮质激素诱导的萎缩。这种抑制的分子细节是 人们对这一点知之甚少，因为每种细胞都使用不同的或重叠的信号转导途径。 受体阻断糖皮质激素受体活性。因此，我们建议：1）确定相对 MuRFt和MAFbx基因对糖皮质激素诱导的骨骼肌萎缩的贡献，2）评估 最近开发的选择性抗炎糖皮质激素受体配体， 萎缩和MuRF 1和MAFbx基因转录，和3）研究的分子细节， 糖皮质激素诱导的MuRF 1基因调控，特别关注以下方面的相反作用： IGF-1和β 2肾上腺素能激动剂。新开发的遗传资源、药理学工具和 分子技术可用于实现这些目标。因此，该提案代表了一个 应用糖皮质激素受体新概念和尖端技术的机会 直接作用于骨骼肌萎缩的高度医学相关问题。