The Complement System and Cancer Cachexia

补体系统和癌症恶病质

基本信息

  • 批准号:
    10537488
  • 负责人:
  • 金额:
    $ 47.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments, and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development of treatments to improve quality of life and enhance survival of cancer patients. However, in exploring the mechanisms that may drive cancer-induced atrophy of myofibers, it is important to do so in the context of the broader muscle pathologies that we and others have shown in the muscle of cachectic tumor bearing hosts, including tissue damage, non-resolute inflammation, impaired regeneration, and increased fat, collagen and calcium deposition. Unpublished proteomics data from our lab collected in the skeletal muscle of cachectic pancreatic cancer patients and, subsequently, cachectic mice bearing pancreatic tumors, releaved an enrichment of multiple pathways of the complement (Cp) system. Further immunohistochemical analyses revealed increased deposition of the central component of the Cp system, C3, and the terminal pathway/membrane attack complex (MAC) within muscle tissues of people and mice with pancreatic tumors, compared to controls. Based on these findings and the established roles of Cp proteins in causing inflammation and tissue damage, we injected mouse pancreatic cancer (KPC) cells into the pancreas of C3 knockout (C3-/-) mice and found significant protection against KPC-induced muscle wasting and weakness, that was further linked to reduced leukocyte infiltration into muscle and reduced fibrotic remodeling. These overall findings establish the requirement of Cp activation for the development of cachexia, with strong translational relevance. Aim 1 will build on these foundational findings and identify the specific Cp activation pathway and effector mechanism(s) required for the development of tumor-induced muscle pathologies and cachexia. This will reveal optimum points in the Cp pathway for pharmacological blockade. Aim 2 will utilize mouse Cp inhibitors that function at different points in the Cp pathway, targeted to sites of Cp deposition, to identify the most effective therapeutic strategy to prevent and reverse cachexia in tumor bearing mice using both the KPC model and C26 adenocarcinoma model. Aim 3 will determine the sufficiency and requirement of local myofiber-derived C3 in pancreatic cancer-induced immune cell infiltration into muscle, muscle damage, atrophy and weakness. This mechanistic aim is important because the role of local myofiber-derived Cp in muscle health and disease is almost completely unknown. Therefore, our findings here will provide mechanistic insights that will enable us to optimize and develop novel Cp inhibitory strategies for the treatment of a broad range of muscle conditions.
项目总结/摘要 恶病质的特征是进行性骨骼肌和体重减轻,影响高达80%的癌症 患者由于这种肌肉质量的损失导致虚弱,对传统治疗的耐受性降低, 和死亡率的增加,了解驱动肌肉萎缩的机制对于发展 提高癌症患者的生活质量和生存率。然而,在探索 尽管存在可能驱动癌症诱导的肌纤维萎缩的机制,但重要的是在癌症的背景下这样做。 我们和其他人已经在恶病质肿瘤携带宿主的肌肉中显示了更广泛的肌肉病理学, 包括组织损伤、非决定性炎症、受损的再生和增加的脂肪、胶原蛋白和 钙沉积我们实验室收集的未发表的恶病质骨骼肌蛋白质组学数据 胰腺癌患者和随后的携带胰腺肿瘤的恶病质小鼠, 富集补体(Cp)系统的多种途径。进一步的免疫组织化学分析 显示增加沉积的中心组成部分的Cp系统,C3,和终端 途径/膜攻击复合物(MAC)在人和小鼠胰腺肿瘤的肌肉组织中, 与对照相比。基于这些发现和Cp蛋白在引起炎症中的既定作用, 和组织损伤,我们将小鼠胰腺癌(KPC)细胞注射到C3敲除(C3-/-)的胰腺中。 小鼠,发现对KPC诱导的肌肉萎缩和虚弱有显着的保护作用,这进一步与 减少白细胞浸润到肌肉中和减少纤维化重塑。这些总体调查结果表明, CP激活的恶病质的发展的要求,具有很强的翻译相关性。目标1将 在这些基础研究结果的基础上,确定特定的Cp激活途径和效应机制 肿瘤诱导的肌肉病变和恶病质的发展所需的。这将揭示最佳点 用于药理学阻断。目的2将利用在不同的细胞周期中起作用的小鼠Cp抑制剂。 点的Cp途径,针对网站的Cp沉积,以确定最有效的治疗策略, 预防和逆转使用KPC模型和C26腺癌模型的荷瘤小鼠的恶病质。 目的3:确定局部肌纤维来源的C3在胰腺癌诱导中的充分性和需求。 免疫细胞渗入肌肉,肌肉受损,萎缩和虚弱。这个机械的目标是重要的 因为局部肌纤维衍生的Cp在肌肉健康和疾病中的作用几乎完全未知。 因此,我们的研究结果将提供机制的见解,使我们能够优化和开发新的 用于治疗广泛肌肉疾病的Cp抑制策略。

项目成果

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Carl Atkinson其他文献

Carl Atkinson的其他文献

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{{ truncateString('Carl Atkinson', 18)}}的其他基金

Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation
将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应
  • 批准号:
    10481101
  • 财政年份:
    2022
  • 资助金额:
    $ 47.71万
  • 项目类别:
Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation
将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应
  • 批准号:
    10693272
  • 财政年份:
    2022
  • 资助金额:
    $ 47.71万
  • 项目类别:
The Complement System and Cancer Cachexia
补体系统和癌症恶病质
  • 批准号:
    10674024
  • 财政年份:
    2022
  • 资助金额:
    $ 47.71万
  • 项目类别:
Complement driven innate and adaptive autoreactivity in lung transplantation
肺移植中补体驱动的先天性和适应性自身反应
  • 批准号:
    10363208
  • 财政年份:
    2021
  • 资助金额:
    $ 47.71万
  • 项目类别:
Complement driven innate and adaptive autoreactivity in lung transplantation
肺移植中补体驱动的先天性和适应性自身反应
  • 批准号:
    10228849
  • 财政年份:
    2020
  • 资助金额:
    $ 47.71万
  • 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
  • 批准号:
    9886648
  • 财政年份:
    2020
  • 资助金额:
    $ 47.71万
  • 项目类别:
Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery
脑死亡相关血管化复合同种异体移植物损伤及其对同种免疫和功能恢复的影响
  • 批准号:
    10293947
  • 财政年份:
    2020
  • 资助金额:
    $ 47.71万
  • 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
  • 批准号:
    10355859
  • 财政年份:
    2020
  • 资助金额:
    $ 47.71万
  • 项目类别:
Epithelial cell complement production in the pathogenesis of chronic rhinosinusitis
慢性鼻窦炎发病机制中上皮细胞补体的产生
  • 批准号:
    10094187
  • 财政年份:
    2020
  • 资助金额:
    $ 47.71万
  • 项目类别:
Brain death associated vascularized composite allograft injury and its impact on alloimmunity and functional recovery
脑死亡相关血管化复合同种异体移植物损伤及其对同种免疫和功能恢复的影响
  • 批准号:
    10399007
  • 财政年份:
    2020
  • 资助金额:
    $ 47.71万
  • 项目类别:

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阐明胰腺腺癌中肿瘤起始细胞和癌症相关成纤维细胞控制的肿瘤进展机制。
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