Novel knockout models to analyze CD38 function

摘要 CD 38是一种多功能的表面糖蛋白，在自身免疫、感染、代谢性疾病等方面发挥重要作用 和癌症，包括临床预后价值。CD 38作为一种受体和胞外酶，调节 烟酰胺腺嘌呤核苷酸（NAD+）的水解和环状ADP-核糖的合成/水解 （cADPR）。CD 38在造血系统中高度保守，并由多种造血谱系表达，包括 B细胞、T细胞、NK细胞、单核细胞、巨噬细胞和树突细胞。全球CD 38缺乏抑制了 多发性硬化（MS）的实验性自身免疫性脑脊髓炎（EAE）动物模型， 导致100万美国人神经功能障碍的中枢神经系统（CNS）疾病。然而，在这方面， 广泛的CD 38表达细胞谱和缺乏条件性CD 38敲除（cKO）模型， 不允许定义负责CD 38功能丧失效应的细胞或机制。解剖细胞 负责CD 38功能丧失治疗效果的靶点将填补这一空白，并通过以下方式使患者受益： 为充分靶向治疗的设计提供信息。淋巴细胞如T/B细胞和单核细胞 巨噬细胞（macrophages）等吞噬细胞（MP）在MS中起关键作用，并可介导MS的致病性。 CD 38的作用有趣的是，我们的实验室最近将CD 38鉴定为小鼠和 促进CNS损伤的人炎性巨噬细胞（M1）。我们假设MP CD 38 表达赋予巨噬细胞致病性表型并促进临床EAE疾病。在 支持这一假设，我们的初步数据显示在EAE期间MP中CD 38表达增加， MP CD 38+表达与EAE严重程度呈正相关。确定髓系CD 38的贡献 对于CNS自身免疫，我们建议（1）产生一种创新的CD 38 floxed小鼠模型， 删除特定细胞类型如MP细胞中的CD 38，以及（2）解决MP细胞CD 38+在 EAE发展。这些模型和发现将提供具有广泛研究影响的资源， CD 38+细胞作为MS中的相关治疗靶点。除了MS，CD 38还在感染中发挥关键作用， 癌症和衰老因此，从这项工作中产生的工具和科学认识是 预计将产生广泛的基础和转化研究的影响。

Abstract CD38 is a multifunctional surface glycoprotein with crucial roles in autoimmunity, infection, metabolic disease and cancer, including clinical prognostic value. CD38 acts as a receptor and as an ectoenzyme regulating the hydrolysis of Nicotinamide Adenine Nucleotide (NAD+) and the synthesis/hydrolysis of cyclic ADP-ribose (cADPR). CD38 is highly conserved in phylogeny and is expressed by multiple hematopoietic lineages, including B cells, T cells, NK cells, monocytes, macrophages and dendritic cells. Global CD38 deficiency suppresses the Experimental Autoimmune Encephalomyelitis (EAE) animal model of Multiple Sclerosis (MS), an inflammatory disease of the central nervous system (CNS) resulting in neurologic disability in 1 million Americans. However, the broad cellular spectrum of CD38 expression and the lack of conditional CD38 knock-out (cKO) models has not allowed to define the cell or mechanism responsible for CD38 loss-of-function effects. Dissecting the cellular targets responsible for CD38 loss-of-function therapeutic effects would fill this gap and benefit patients by informing the design of adequately targeted therapies. Both lymphoid cells such as T/B cells and mononuclear phagocyte (MP) cells such as macrophages play critical roles in MS and could mediate the pathogenic effects of CD38. Interestingly, our laboratory recently identified CD38 as a selective marker of mouse and human inflammatory macrophages (M1) that promote CNS damage. We hypothesize that MP CD38 expression confers pathogenic phenotype to macrophages and promotes clinical EAE disease. In support of this hypothesis, our preliminary data show increased CD38 expression in MP during EAE and a positive link between MP CD38+ expression and EAE severity. To define the contribution of myeloid CD38 to CNS autoimmunity, we propose to (1) generate an innovative CD38 floxed mouse model to conditionally delete CD38 in specific cell types such as MP cells and (2) address the impact of MP cell CD38+ during EAE development. These models and findings will provide resources of broad research impact and define MP CD38+ cells as a relevant therapeutic target in MS. Beyond MS, CD38 also plays crucial roles in infection, cancer and aging. Therefore, the tools and scientific understanding stemming from this work are expected to have broad basic and translational research impact.