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：
8513316
负责人：
Theodore Paul Braun
金额：
$ 4.36万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513316
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）：这项研究的目的是了解中央黑色皮质素系统在卡氏症中肌肉发病机理中的作用。患者保持瘦质量的能力是生活质量的重要因素，也是生存的重要预测指标。目前，没有治疗性干预措施可以改善慢性疾病中的瘦质量。黑素皮质素系统在食欲和基础代谢率中的作用已经很好地确定，但是它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检查。黑色皮质素4受体（MC4R）敲除小鼠具有增加的瘦质量表型，并且对缓存中瘦质量的损失具有抵抗力。黑色皮质素受体的药理阻滞也可以改善实验诱导的恶病质。对肌肉崩溃的发病机理至关重要的是肌肉特异性E3泛素连接酶，MAFBX和MURF-1.1表明，中枢性黑色素素系统的药理学激活诱导这些基因在骨骼肌中的表达。黑色素皮质信号传导通过信号传导介质AMPK和FOXO转录因子家族介导的黑色素性信号传导影响肌肉的神经解剖途径可能是由交感神经系统介导的。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来改变。在药理学黑素性激活的情况下，将检查中央黑色皮质素影响肌肉质量的信号传导途径。然后，在存在和不存在黑色素皮质蛋白阻滞的情况下，将在实验恶病质动物模型中检查建立的信号通路。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单途径。最后，该途径的神经元连通性将通过使用逆行轨迹追踪方法来检查。假病毒将被注射到MC4R-GFP转基因小鼠的肌肉中，并将检查下丘脑中MC4R阳性神经元的感染。这项工作将有助于更清楚地了解卡氏症中肌肉浪费的神经成分。对这一途径的机械理解将为这些患者的护理提供深入的了解，并为理性药物设计提供了未来的目标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

P-selectin genotype is associated with the development of cancer cachexia.

P-选择素基因型与癌症恶病质的发生有关。

DOI：
10.1002/emmm.201200231
发表时间：
2012
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Tan,BenjaminHL;Fladvad,Torill;Braun,TheodoreP;Vigano,Antonio;Strasser,Florian;Deans,DAChristopher;Skipworth,RichardJE;Solheim,ToraS;Damaraju,Sambasivarao;Ross,JamesA;Kaasa,Stein;Marks,DanielL;Baracos,VickieE;Skorpen,F
通讯作者：
Skorpen,F

Pathophysiology and treatment of inflammatory anorexia in chronic disease.