The Role of the Central Melanocortin System in the Muscle Wasting of Cachexia

中枢黑皮质素系统在恶病质肌肉萎缩中的作用

基本信息

批准号：
8113998
负责人：
Theodore Paul Braun
金额：
$ 4.45万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113998
关键词：
Address Adipose tissue Adrenergic Receptor Affect Agonist Area Basal metabolic rate Cachexia Cancer Model Catabolism Chronic Chronic Disease Complication Cytokine Signaling Dependence Desire for food Disease Disease model Drug Design Endocrine Equilibrium Etiology Experimental Animal Model FOS gene Family Future Gene Expression Genes Goals Human Hypothalamic structure Infection Inflammatory Knockout Mice Label Lead Malignant Neoplasms Malnutrition Measures Mediating Mediator of activation protein Melanocortin 4 Receptor Metabolic Metabolism Molecular Morbidity - disease rate Muscle Neural Pathways Neurons Neuropeptides Pathogenesis Pathway interactions Patient Care Patients Pattern Phenotype Population Process Proteins Proteolysis Quality of life Rattus Regulation Relative (related person)Research Resistance Role Severities Signal Pathway Signal Transduction Skeletal Muscle Starvation Suid Herpesvirus 1 Sympathetic Nervous System System Therapeutic Intervention Time Tissues Transgenic Mice Western Blotting Work cytokine energy balance improved increased appetite insight loss of function mutation melanocortin receptor muscle form nerve supply new therapeutic target relating to nervous system research study transcription factor ubiquitin-protein ligase wasting

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to understand the role of the central melanocortin system In the pathogenesis of muscle wasting in cachexia. A patient's ability to maintain lean mass is an important factor in quality of life as well as an important predictor of survival. Currently there are no therapeutic interventions that can improve lean mass retention in chronic disease. The role of the melanocortin system in appetite and basal metabolic rate is well established, but its role in the regulation of the anabolic/catabolic balance of muscle has not been fully examined. Melanocortin 4 receptor (MC4R) knockout mice have an increased lean mass phenotype, and are resistant to loss of lean mass in cachexia. Pharmacologic blockade of melanocortin receptors also ameliorates experimentally-induced cachexia. Critical to the pathogenesis of muscle breakdown are the muscle specific E3 ubiquitin ligases, MAFbx and MuRF-1.1 have shown that pharmacological activation of the central melanocortin system induces expression of these genes in skeletal muscle. The neuroanatomical pathway by which melanocortin signaling influences muscle is likely to be mediated by the sympathetic nervous system, via the signaling mediators AMPK and the FOXO family of transcription factors. Therefore I will investigate whether the transduction of this signal can be altered by the presence of sympathetic blockade. A signaling pathway by which central melanocortins influence muscle mass will be examined in the setting of pharmacologic melanocortin activation. The signaling pathway established will then be examined in an animal model of experimental cachexia in the presence and absence of melanocortin blockade. By comparing pharmacologic activation to the disease model, a common molecular singnaling pathway in muscle will be identified. Finally, the neuronal connectivity of this pathway will be examined by utilizing a retrograde track tracing approach. Pseudorabies virus will be injected into muscle of MC4R-GFP transgenic mice, and infection of MC4R-positive neurons in the hypothalamus will be examined. This work will help develop a clearer understanding of the neural component of muscle wasting in cachexia. A mechanistic understanding of this pathway will provide insight into the care of these patients and provide future targets for rational drug design.

描述（由申请人提供）：本研究的目的是了解中枢黑皮质素系统在恶病质肌肉萎缩发病机制中的作用。患者维持瘦体重的能力是生活质量的重要因素，也是生存的重要预测因素。目前还没有可以改善慢性疾病的瘦体重保留的治疗干预措施。黑皮质素系统在食欲和基础代谢率中的作用已得到充分证实，但其在调节肌肉合成代谢/分解代谢平衡中的作用尚未得到充分研究。黑皮质素 4 受体 (MC4R) 敲除小鼠的瘦体重表型增加，并且能够抵抗恶病质时瘦体重的损失。黑皮质素受体的药物阻断也可改善实验诱发的恶病质。肌肉分解的发病机制至关重要的是肌肉特异性 E3 泛素连接酶、MAFbx 和 MuRF-1.1 已表明，中枢黑皮质素系统的药理激活会诱导这些基因在骨骼肌中的表达。黑皮质素信号传导影响肌肉的神经解剖学途径可能是由交感神经系统通过信号传导介质 AMPK 和转录因子 FOXO 家族介导的。因此，我将研究该信号的转导是否可以通过交感神经阻滞的存在而改变。将在药理学黑皮质素激活的背景下检查中枢黑皮质素影响肌肉质量的信号通路。然后将在存在或不存在黑皮质素阻断的实验性恶病质动物模型中检查所建立的信号通路。通过将药理学激活与疾病模型进行比较，将确定肌肉中常见的分子信号传导途径。最后，将利用逆行轨迹追踪方法检查该通路的神经元连接。将伪狂犬病病毒注射到MC4R-GFP转基因小鼠的肌肉中，并检查下丘脑中MC4R阳性神经元的感染情况。这项工作将有助于更清楚地了解恶病质中肌肉萎缩的神经成分。对这一途径的机械理解将有助于深入了解这些患者的护理，并为合理的药物设计提供未来的目标。