Coordination Funds

拟议的研究单位的目标是阐明代谢和信号信号如何整合在调节B细胞命运和功能的过程中。B细胞是对病原体的体液免疫的中心参与者，但也可以在不同的自身免疫性疾病和恶性肿瘤中发展/发挥病理作用。过去在研究B细胞信号转导方面的广泛努力已经为这些疾病的患者提供的许多靶向治疗铺平了道路，直到今天。然而，由于B细胞功能的复杂和多方面的阵列，B细胞驱动的疾病仍然是一个临床挑战。免疫代谢的研究代表了一个令人信服的机会来识别新的调节节点来微调B细胞的反应。拟议的研究单位将专注于新陈代谢如何塑造B细胞功能的两个重叠方面。首先，我们将评估微环境如何影响B细胞的命运决定。不同器官的新陈代谢状况各不相同，可能会随着全身新陈代谢或炎症等病理过程的改变而改变。营养和氧气的可获得性不仅对能量和生物合成前体分子的产生至关重要，而且还积极参与决定细胞的命运。我们的目标是确定营养和氧气的获取如何影响生发中心、骨髓或发炎肾脏等复杂免疫利基中的B细胞。在第二个补充研究中，我们试图定义信号和代谢机制如何相互作用的分子基础。钙稳态、NAD(P)水平和活性氧的产生是代谢和信号传递过程的中心，但目前还缺乏一个全面的模型来说明它们在连接B细胞生物学的这些基本方面中所起的作用。我们将借鉴相关项目负责人在特定疾病模型、实验技术和B细胞信号调节机制方面的长期专业知识，以实现拟议的目标，并合作探索信号与新陈代谢之间的接口。我们的总体目标是提供一个B细胞中信号转导和代谢之间的功能相互作用的模型，以允许利用自身免疫和恶性B细胞的代谢脆弱性进行治疗。

The goal of the proposed research unit is to elucidate how metabolic and signaling cues are integrated in regulating B cell fate and function. B cells are central players of humoral immunity to pathogens, but can also develop/ take pathologic roles in different autoimmune disorders and malignancies. Extensive efforts in studying B cell signal transduction in the past have paved the way for many of the targeted therapies available to patients of these diseases until today. Yet, B cell driven disorders remain a clinical challenge due to the complex and multifaceted array of B cell functions. The study of immunometabolism represents a compelling opportunity to identify new regulatory nodes to fine-tune B cell responses. The proposed research unit will focus on two overlapping aspects of how metabolism can shape B cell function. First, we will assess how the microenvironment affects B cell fate decisions. Metabolic conditions vary between different organs and can change in response to altered whole body metabolism or pathologic processes such as inflammation. Nutrient and oxygen availability are not only crucial for the generation of energy and biosynthetic precursor molecules, but also actively participate in shaping cell fate decisions. Our goal is to define how access to nutrients and oxygen affects B cells in complex immunological niches such as the germinal center, the bone marrow or inflamed kidneys. In a second complimentary line of investigation, we seek to define the molecular underpinnings of how the signaling and metabolic machinery interact. Ca2+ homeostasis, NAD(P) levels and the production of reactive oxygen species are central to both metabolic- and signaling- processes, yet a comprehensive model of their role in connecting these fundamental aspects of B cell biology is currently missing. We will draw on the long-standing expertise of the involved project leaders in specific disease models, experimental techniques and regulatory mechanisms of B cell signaling to reach the proposed goals and to collaboratively explore the interface between signaling and metabolism. Our overarching aim is to provide a model of the functional interplay between signal transduction and metabolism in B cells that would allow to exploit metabolic vulnerabilities of autoimmune and malignant B cells for therapy.