Coordination Funds

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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.