Novel knockout models to analyze CD38 function

用于分析 CD38 功能的新型敲除模型

• 批准号: 10177865
• 负责人: Mireia Guerau-de-Arellano
• 金额: $ 7.8万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-03 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177865
• 关键词: Address; Adenine Nucleotides; Aging; Alleles; American; Animal Model; Autoimmune; Autoimmunity; B-Lymphocytes; Basic Science; CNS autoimmunity; Cell Therapy; Cells; Central Nervous System Diseases; Chronic; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cyclic ADP-Ribose; Data; Dendritic Cells; Development; Disease; Enzymes; Experimental Autoimmune Encephalomyelitis; FDA approved; Flow Cytometry; Generations; Hematologic Neoplasms; Hematopoietic; Human; Hydrolysis; Immune response; Infection; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Laboratories; Link; LoxP-flanked allele; Lupus; Lymphoid Cell; Malignant Neoplasms; Measures; Mediating; Membrane Glycoproteins; Metabolic; Metabolic Diseases; Microglia; Modeling; Mononuclear; Multiple Sclerosis; Mus; Myelogenous; Natural Killer Cells; Nervous System Trauma; Neuraxis; Neurologic; Niacinamide; Ohio; Oxidative Phosphorylation; Oxidative Stress; Pathogenicity; Patients; Peripheral; Phagocytes; Pharmaceutical Preparations; Phenotype; Phylogeny; Play; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Resources; Rodent; Role; Severities; Severity of illness; T-Lymphocyte; Testing; Therapeutic Effect; Tissues; Translational Research; Universities; Work; cell type; cellular targeting; chemokine; cytokine; defined contribution; design; disability; homologous recombination; inflammatory marker; innovation; interest; loss of function; macrophage; monocyte; mouse model; novel; nucleotide metabolism; prognostic; prognostic value; receptor; stem; success; targeted treatment; therapeutic target; tool

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.

摘要 CD38是一种多功能表面糖蛋白，在自身免疫、感染、代谢性疾病中起重要作用 和癌症，包括临床预后价值。CD38作为受体和胞外酶调节 烟酰胺腺嘌呤核苷酸(NAD+)的水解及环状ADP-核糖的合成/水解 (Cadpr)。CD38在系统发育中高度保守，由多种造血系表达，包括 B细胞、T细胞、NK细胞、单核细胞、巨噬细胞和树突状细胞。全球CD38缺陷抑制了 炎症性多发性硬化症的实验性自身免疫性脑脊髓炎动物模型 中枢神经系统(CNS)疾病导致100万美国人神经性残疾。然而， CD38表达的广泛细胞谱和缺乏条件性CD38基因敲除(CKO)模型 不允许定义CD38功能丧失效应的细胞或机制。解剖细胞 负责CD38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 告知充分有针对性的治疗方案的设计。T/B细胞等淋巴样细胞和单个核细胞 巨噬细胞等吞噬细胞在多发性硬化症中起着关键作用，并可介导致病因子 CD38的作用。有趣的是，我们的实验室最近发现CD38是小鼠和 促进中枢神经系统损伤的人类炎性巨噬细胞(M1)。我们假设MP CD38 表达赋予巨噬细胞致病表型，并促进临床EAE疾病。在……里面 支持这一假设，我们的初步数据显示，在EAE和A MP CD38+表达与EAE病情严重程度呈正相关。确定髓系CD38的贡献 对于CNS自身免疫，我们建议(1)建立一种创新的CD38绒毛小鼠模型，以有条件地 删除特定细胞类型中的CD38，如MP细胞和(2)解决MP细胞CD38+在 EAE开发。这些模型和发现将提供具有广泛研究影响的资源，并定义MP CD38+细胞作为MS的相关治疗靶点，除MS外，CD38在感染中也起着关键作用， 癌症和衰老。因此，这项工作产生的工具和科学理解是 预计将产生广泛的基础研究和翻译研究影响。

项目成果

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions.

• DOI: 10.1002/acn3.51338
• 发表时间: 2021-04
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Gillen KM;Mubarak M;Park C;Ponath G;Zhang S;Dimov A;Levine-Ritterman M;Toro S;Huang W;Amici S;Kaunzner UW;Gauthier SA;Guerau-de-Arellano M;Wang Y;Nguyen TD;Pitt D
• 通讯作者: Pitt D

CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity.

• DOI: 10.3389/fimmu.2020.597959
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Piedra-Quintero ZL;Wilson Z;Nava P;Guerau-de-Arellano M
• 通讯作者: Guerau-de-Arellano M

Akt isoforms in the immune system.

• DOI: 10.3389/fimmu.2022.990874
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Guerau-de-Arellano, Mireia;Piedra-Quintero, Zayda L. L.;Tsichlis, Philip N.
• 通讯作者: Tsichlis, Philip N.

Corticosteroid insensitivity persists in the absence of STAT1 signaling in severe allergic airway inflammation.

• DOI: 10.1152/ajplung.00244.2021
• 发表时间: 2021-12-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Lewis BW;Jackson D;Amici SA;Walum J;Guessas M;Guessas S;Coneglio E;Boda AV;Guerau-de-Arellano M;Grayson MH;Britt RD Jr
• 通讯作者: Britt RD Jr

Protein Arginine Methyltransferase 5 in T Lymphocyte Biology.

• DOI: 10.1016/j.it.2020.08.007
• 发表时间: 2020-10
• 期刊: TRENDS IN IMMUNOLOGY
• 影响因子: 16.8
• 作者: Sengupta, Shouvonik;Kennemer, Austin;Patrick, Kristin;Tsichlis, Philip;Guerau-de-Arellano, Mireia
• 通讯作者: Guerau-de-Arellano, Mireia