cAMP/PKA mediated signaling in B cell metabolism and function.

cAMP/PKA 介导 B 细胞代谢和功能中的信号传导。

• 批准号: 419193696
• 负责人: Professorin Dr. Julia Jellusova
• 金额: --
• 依托单位: Institut für Klinische Chemie und Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419193696?language=en
• 关键词: cAMP; PKA; mediated; signaling; cell

Activated lymphocytes face considerable metabolic challenges and need to be able to adjust their metabolic activity in a dynamic manner. Increasing evidence suggests that nutrient acquisition and utilization is not simply a passive process in lymphocytes, but is tightly regulated by various intracellular signaling pathways. The goal of the proposed project is to systematically analyze how cAMP/PKA mediated signaling contributes to the regulation of B cell metabolism and function. cAMP is a ubiquitous signaling molecule known to activate protein kinase A (PKA). cAMP-dependent signaling has been implicated to regulate different aspects of cell function and metabolism, however surprisingly little is known about cAMP signaling in B cells. Our preliminary data suggest that PKA inhibition leads to impaired mitochondrial function and ultimately cell death in activated B cells. Surprisingly however, cAMP mediated PKA activation has profoundly different effects on B cell viability and proliferation depending on the signaling context. The goal of the project is to define PKA-dependent and independent signaling pathways downstream of cAMP in normal and malignant B cells and to elucidate the role of cAMP and PKA in regulating mitochondrial function and metabolic activity. Moreover, cell metabolism not only supports proliferation, but often guides cell fate decisions and effector functions. In our previous studies, we have shown that B cells are exposed to changes in their metabolic environment during the germinal center response and that appropriate responses to metabolic challenges are necessary to maintain B cell viability. Our aim is to analyze how nutrient and oxygen availability affect activation of the cAMP/PKA signaling pathway and how these environmental cues are integrated with cytokine induced signaling. In summary, this project will yield novel insights into the regulation of cell metabolism in normal and malignant B cells. A better understanding of metabolic adaptations in B cells is essential in order to identify metabolic vulnerabilities in cancer cells and novel avenues for immunomodulation.

活化淋巴细胞面临相当大的代谢挑战，需要能够以动态的方式调整其代谢活性。越来越多的证据表明，在淋巴细胞中，营养物质的获取和利用不仅仅是一个被动的过程，而是受到多种细胞内信号通路的严格调控。本项目的目标是系统分析cAMP/PKA介导的信号如何参与B细胞代谢和功能的调节。cAMP是一种普遍存在的信号分子，可以激活蛋白激酶a （PKA）。cAMP依赖的信号传导与细胞功能和代谢的不同方面有关，然而令人惊讶的是，我们对B细胞中的cAMP信号传导知之甚少。我们的初步数据表明，PKA抑制导致活化B细胞线粒体功能受损，最终导致细胞死亡。然而，令人惊讶的是，cAMP介导的PKA活化对B细胞的活力和增殖有截然不同的影响，这取决于信号传导环境。该项目的目标是确定正常和恶性B细胞中cAMP下游的PKA依赖和独立信号通路，并阐明cAMP和PKA在调节线粒体功能和代谢活性中的作用。此外，细胞代谢不仅支持细胞增殖，而且经常指导细胞的命运决定和效应功能。在我们之前的研究中，我们已经证明B细胞在生发中心反应期间暴露于代谢环境的变化中，并且对代谢挑战的适当反应是维持B细胞活力所必需的。我们的目的是分析营养和氧气的可用性如何影响cAMP/PKA信号通路的激活，以及这些环境线索如何与细胞因子诱导的信号通路相结合。总之，该项目将对正常和恶性B细胞的细胞代谢调节产生新的见解。更好地了解B细胞的代谢适应对于确定癌细胞的代谢脆弱性和免疫调节的新途径至关重要。