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

活化的淋巴细胞面临着相当大的代谢挑战，需要能够以动态的方式调整自己的代谢活动。越来越多的证据表明，营养物质的获取和利用在淋巴细胞中不是一个简单的被动过程，而是受到各种细胞内信号通路的严格调控。该项目的目标是系统分析cAMP/PKA介导的信号如何在B细胞代谢和功能调节中发挥作用。CAMP是一种普遍存在的信号分子，可激活蛋白激酶A(PKA)。CAMP依赖的信号转导与细胞功能和代谢的不同方面有关，然而令人惊讶的是，人们对B细胞中的cAMP信号知之甚少。我们的初步数据表明，抑制PKA会导致激活的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激活对B细胞活性和增殖的影响因信号背景而异。该项目的目标是确定正常和恶性B细胞中依赖于PKA的和独立的cAMP下游信号通路，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，细胞新陈代谢不仅支持增殖，而且经常指导细胞命运决定和效应器功能。在我们之前的研究中，我们已经证明B细胞在生发中心的反应中暴露于其代谢环境的变化中，并且对代谢挑战的适当反应对于维持B细胞的活性是必要的。我们的目的是分析营养和氧气供应如何影响cAMP/PKA信号通路的激活，以及这些环境信号是如何与细胞因子诱导的信号相结合的。综上所述，该项目将为调节正常和恶性B细胞的细胞代谢提供新的见解。为了识别癌细胞的代谢脆弱性和免疫调节的新途径，更好地了解B细胞的代谢适应是必不可少的。

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.