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SFB 1328:  Adenine Nucleotides in Immunity and Inflammation

Subject Area Biology
Chemistry
Medicine
Term since 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 335447717
 
Extracellular and intracellular adenine nucleotides (AN) impact on all central processes in biology and medicine. AN are essential and ubiquitous signaling molecules involved in regulating universal cellular processes, including cell-cell communication and intracellular signaling. The central goal of the research consortium is to enhance our understanding of the regulatory roles of AN in the context of inflammatory diseases. Specific aims relate to (i) modulation of the balance between pro- and anti-inflammatory processes by AN converting ecto-nucleotidases and purinergic receptors, and to (ii) AN-driven intracellular Ca2+ signaling and 3’,5’-cyclic adenosine monophosphate (cAMP) signaling in inflammation. In the 2nd funding period we concentrated on AN action in space and time during inflammation, AN-regulated interplay of inflammatory and stromal cells, and applied newly identified and/or validated compounds or molecular targets in selected inflammatory disease models. Major results are summarized below. The danger molecule ATP increases speed of migration of dendritic cells. Projects A06, A16, A20, and A21 showed that migratory dendricitc cells (DC) can be distinguished from other DC subsets and immune cells by their expression of the voltage-gated Ca2+ channel subunit β3, which exclusively facilitates ATP-dependent migration in vitro and during tissue damage in vivo. Another major breakthrough was made possible by collaborative efforts of projects A01, A02, A03, A04, and A21 through the development and validation of MASTER-NAADP, a Membrane permeAble, STabilized, biorEversibly pRotected precursor of nicotinic acid adenine dinucleotide phosphate (NAADP). Further projects A01, A02, A03, A04, A06, and A11 discovered that NAADP signaling in T cells requires the integration of TCR/CD28-independent and -dependent, local signals, that coincide at the level of the dual NADPH oxidase 2. In cAMP signaling, projects A09, A10, and A11 discovered that enhanced expression of the thermogenic program in healthy adipocytes is mediated by inosine and that EPAC1 is a central regulator of thermogenic fat mass and thus a promising therapeutic target. Further, PIs organized congresses in the field of AN, e.g. the recent FASEB Research Conference on ‘NAD Metabolism and Signaling 2024’ organized by the CRC speaker Andreas Guse in August 2024 or the World Congress on Purines 2025 that was co-organized by Christian Lohr and Christa Müller. Taken together, many more gaps and white spots on the landscape of AN biology and pathophysiology have been filled, allowing, as overarching aims for the 3rd funding period: (i) the development of an integral view of AN biology and pathophysiology, and (ii) application of the new druggable targets and modulators of AN function to disease. The latter is possible by a highly engaged core team of CRC1328 from Hamburg that will be markedly strengthened by excellent colleagues from Bonn, Göttingen, Munich, and Heidelberg.
DFG Programme Collaborative Research Centres

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Applicant Institution Universität Hamburg
 
 

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