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:
    7750694
  • 负责人:
  • 金额:
    $ 4.14万
  • 依托单位:
  • 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

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。目前还没有治疗干预措施可以改善慢性疾病中的瘦体重保持。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,但其在肌肉合成代谢/分解代谢平衡调节中的作用尚未得到充分研究。 黑皮质素4受体(MC 4 R)敲除小鼠具有增加的瘦体重表型,并且对恶病质中的瘦体重损失具有抗性。黑皮质素受体的药理学阻断也改善实验诱导的恶病质。肌肉分解的发病机制的关键是肌肉特异性E3泛素连接酶,MAFbx和MuRF-1.1已经表明,中枢黑皮质素系统的药理学激活诱导骨骼肌中这些基因的表达。黑皮质素信号传导影响肌肉的神经解剖学途径可能由交感神经系统通过信号传导介质AMPK和转录因子的FOXO家族介导。因此,我将研究是否可以通过交感神经阻滞的存在改变这种信号的转导。中枢黑皮质素影响肌肉质量的信号通路将在药理学黑皮质素激活的背景下进行检查。然后,在存在和不存在黑皮质素阻断的情况下,在实验性恶病质的动物模型中检查所建立的信号传导途径。通过比较药理学活化与疾病模型,将鉴定肌肉中的共同分子信号传导途径。最后,这一途径的神经元连接将通过利用逆行追踪方法进行检查。将伪狂犬病病毒注射到MC 4 R-GFP转基因小鼠的肌肉中,并检查下丘脑中MC 4 R阳性神经元的感染。 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。对这一途径的机制理解将为这些患者的护理提供深入了解,并为合理的药物设计提供未来的目标。

项目成果

期刊论文数量(0)
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Theodore Paul Braun其他文献

Theodore Paul Braun的其他文献

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{{ truncateString('Theodore Paul Braun', 18)}}的其他基金

Dual Kinase and LSD1 Inhibition in Acute Myeloid Leukemia
急性髓系白血病的双重激酶和 LSD1 抑制
  • 批准号:
    10716085
  • 财政年份:
    2023
  • 资助金额:
    $ 4.14万
  • 项目类别:
Epigenetics of Mutation-Order in Acute Myeloid Leukemia
急性髓系白血病突变顺序的表观遗传学
  • 批准号:
    10596588
  • 财政年份:
    2020
  • 资助金额:
    $ 4.14万
  • 项目类别:
Epigenetics of Mutation-Order in Acute Myeloid Leukemia
急性髓系白血病突变顺序的表观遗传学
  • 批准号:
    10379071
  • 财政年份:
    2020
  • 资助金额:
    $ 4.14万
  • 项目类别:
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
  • 批准号:
    8513316
  • 财政年份:
    2009
  • 资助金额:
    $ 4.14万
  • 项目类别:
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
  • 批准号:
    8113998
  • 财政年份:
    2009
  • 资助金额:
    $ 4.14万
  • 项目类别:
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
  • 批准号:
    8305618
  • 财政年份:
    2009
  • 资助金额:
    $ 4.14万
  • 项目类别:

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