SFB 1328: Adenine Nucleotides in Immunity and Inflammation

细胞外和细胞内的腺嘌呤核苷酸（adenine nucleotides，AN）是一种重要的、普遍存在的信号分子，参与调节包括细胞间通讯和细胞内信号传导在内的各种细胞过程。我们的中心目标是加强对AN在炎症性疾病中的调节作用的理解。具体目标涉及（i）促炎和抗炎嘌呤能信号传导过程，以及（ii）炎症中AN驱动的细胞内Ca 2+信号传导和3 '，5'-环腺苷酸（cAMP）信号传导。在第一个资助期间发现的新颖性是腺苷（ADO）产生的CD 73对T细胞衍生的细胞外囊泡的抗炎作用。此外，在中风动物模型中，在实验性自身免疫性脑脊髓炎中，以及在脂肪组织中的代谢和炎症反应期间观察到促炎性嘌呤能信号传导。烟酸腺嘌呤二核苷酸磷酸（NAADP）形成酶和NAADP受体/结合蛋白被鉴定为双NADPH氧化酶2（DUOX 2）和HN 1 L/JPT 2。在第二个资助期，我们将确定ATP和ADO在T细胞可塑性、肥大细胞和巨噬细胞活化或树突状细胞迁移中的作用，以及在肠道、脂肪组织和中枢神经系统（CNS）炎症过程中的作用。将探讨CD 73和含CD 73的细胞外囊泡在这些过程中的抗炎活性。此外，将研究ATP通过P2 X和P2 Y受体的促炎作用。值得注意的是，新的ATP传感器和ATP降解CD 39的调节剂将被合成和评估。将研究通过DUOX 2、HN 1 L/JPT 2、1型ryanodine受体和T细胞、肥大细胞和树突状细胞中的双孔通道的NAADP依赖性Ca 2+信号传导的分子细节。将探讨NAADP依赖性Ca 2+信号传导对肠道和CNS炎症中免疫细胞可塑性和功能的下游影响。此外，将研究Ca 2+进入过程。此外，TRPM 2信号的结构基础将被确定。一个重要的延续是NAADP和ADPR的膜渗透前药的开发。在T细胞、星形胶质细胞、神经元和棕色脂肪细胞中，cAMP信号传导的新分子细节将被研究，重点是cAMP的抗炎作用。来自汉堡的CRC 1328的核心团队将得到来自波恩、哥廷根、慕尼黑和海德堡的同事的大力加强。通过跨学科的整合，我们将共同开发AN生物学和病理生理学的全面观点，为免疫，肠道，脂肪和神经系统炎症性疾病的新型诊断和治疗策略提供基础。

Extracellular and intracellular adenine nucleotides (AN) are essential and ubiquitous signaling molecules involved in regulating universal cellular processes, including cell-cell communication and intracellular signaling. Our central goal is to enhance understanding of the regulatory roles of AN in the context of inflammatory diseases. Specific aims relate to (i) pro- and anti-inflammatory purinergic signaling processes, and to (ii) AN-driven intracellular Ca2+ signaling and 3’,5’-cyclic adenosine monophosphate (cAMP) signaling in inflammation. Novelties discovered during the 1st funding period are an anti-inflammatory role of adenosine(ADO)-producing CD73 on extracellular vesicles derived from T cells. Further, pro-inflammatory purinergic signaling was observed in a stroke animal model, in experimental autoimmune encephalomyelitis, and during metabolic and inflammatory responses in adipose tissue.The nicotinic acid adenine dinucleotide phosphate (NAADP) forming enzyme and the NAADP receptor/binding protein were identified as dual NADPH oxidase 2 (DUOX2) and HN1L/JPT2. Antagonizing NAADP resulted in transdifferentiation of effector T cells into regulatory T cells, a novel mechanism with anti-inflammatory potential.In the 2nd funding period we will define roles of purinergic signaling by ATP and ADO in T cell plasticity, mast cell and macrophage activation, or dendritic cell migration, and during inflammation of intestine, adipose tissue and central nervous system (CNS). The anti-inflammatory activity of CD73 and of CD73-containing extracellular vesicles in these processes will be explored. Further, pro-inflammatory effects of ATP via P2X and P2Y receptors will be studied. Of note, novel ATP sensors and modulators of ATP-degrading CD39 will be synthesized and evaluated. Molecular details of NAADP dependent Ca2+ signaling via DUOX2, HN1L/JPT2, type 1 ryanodine receptor, and two-pore channels in T cells, mast cells and dendritic cells will be studied. Downstream effects of NAADP-dependent Ca2+ signaling on immune cell plasticity and function in intestinal and CNS inflammation will be explored. In addition, Ca2+ entry processes will be studied. Further, the structural basis of TRPM2 signaling will be determined. An important continuation is the development of membrane-permeant prodrugs of NAADP and ADPR. In T cells, astrocytes, neurons and brown adipocytes, novel molecular details of cAMP signaling will be investigated, with emphasis on anti-inflammatory effects of cAMP.The core team of CRC1328 from Hamburg will be significantly strengthened by colleagues from Bonn, Göttingen, Munich, and Heidelberg. Together, and by interdisciplinary integration we will develop a comprehensive view of AN biology and pathophysiology, providing the basis for novel diagnostic and treatment strategies for inflammatory diseases in immune, intestinal, adipose and nervous systems.