The role of the intracellular complement system - the complosome - in monocytes

细胞内补体系统（复合体）在单核细胞中的作用

• 批准号: 10008830
• 负责人: Claudia Kemper
• 金额: $ 18.57万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10008830
• 关键词: Arteries; Biological; Biology; Candida; Cardiovascular Diseases; Cells; Collaborations; Complement; Development; Event; Eye; Future; Goals; Human; In Vitro; Infection; Inflammation; International; Intervention; Laboratories; Medical; Mitochondria; Molecular; Mus; Pathway interactions; Peptide Hydrolases; Permeability; Pre-Clinical Model; Production; Regulation; Role; Signal Transduction; Sterility; T cell response; T-Lymphocyte; Technology; Testing; United States National Institutes of Health; chronic infection; complement system; experimental study; in vivo; inhibitor/antagonist; macrophage; monocyte; mouse model; novel; novel therapeutics; preclinical development

Our laboratory has identified a novel role for intracellular complement activity in the regulation of human T cell responses. In collaboration with groups from within the NIH and international collaborators, we have now extended this finding and defined a role for the intracellular C5ar1 also in normal human and mouse monocyte biology. Intracellular C5ar1 signaling on mitochondria is required for optimal IL-1beta production during infection but also sterile inflammation. We are currently assessing the in vivo biological significance of this observation using appropriate infection (candida) and CVD mouse models. We are also testing the effects of cell-permeable C5 inhibitors in vitro with an eye on the development of preclinical models. We have also made progress in defining how exactly C5 is activated intracellularly in monocytes and T cells and are performing final experiments with cells in which the candidate protease has been deleted by CRISP-Cas9 technology. The better understanding of the key roles of intracellular C5 activity and its regulation will potentially allow for the development of new therapies in infection/chronic inflammation.

我们的实验室已经确定了细胞内补体活性在调节人类T细胞反应中的一个新的作用。在与美国国立卫生研究院和国际合作者的合作下，我们现在扩展了这一发现，并确定了细胞内C5ar1在正常人类和小鼠单核细胞生物学中的作用。线粒体上的细胞内C5ar1信号是感染期间产生最佳IL-1β所必需的，也是无菌炎症所必需的。我们目前正在使用适当的感染(念珠菌)和CVD小鼠模型来评估这一观察的体内生物学意义。我们还在体外测试细胞渗透性C5抑制剂的效果，着眼于临床前模型的发展。 我们还在确定C5在单核细胞和T细胞中如何被细胞内激活方面取得了进展，并正在对候选蛋白酶已被CRISP-Cas9技术删除的细胞进行最后的实验。 更好地了解细胞内C5活性及其调节的关键作用，将可能有助于开发新的感染/慢性炎症治疗方法。