Identification of novel Inhibitory receptors Involved In B cell tolerance

鉴定参与 B 细胞耐受的新型抑制性受体

• 批准号: 10056152
• 负责人: Andrew Getahun
• 金额: $ 22.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-09 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056152
• 关键词: Adaptor Signaling Protein; Affect; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Binding; Chromatin; Combined Modality Therapy; Data; Dependence; Development; Diabetes Mellitus; Disease; Early Intervention; Early identification; Environmental Risk Factor; Equilibrium; Event; Feedback; Genetic; Goals; ITIM; Immune Tolerance; Individual; Inositol; Knowledge; Lead; Lipids; Lupus; Maintenance; Mass Screening; Mass Spectrum Analysis; Mediating; Molecular; Mus; PTPN6 gene; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological Processes; Play; Preventive care; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Rheumatoid Arthritis; Risk; Role; Signal Transduction; Specificity; Systemic Lupus Erythematosus; Techniques; Therapeutic Intervention; Transmembrane Domain; Tyrosine; anergy; autoreactive B cell; base; differential expression; humoral immunity deficiency; in vivo; insight; lupus-like; man; new therapeutic target; novel; peripheral tolerance; prevent; receptor; recruit; risk variant; src Homology Region 2 Domain; src-Family Kinases; targeted treatment; therapeutic candidate

Project Summary Both genetic and environmental factors conspire during early stages of autoimmune disease to break immune tolerance. Several risk alleles associated with an increased risk of developing systemic lupus erythematosus (SLE), and other autoimmune diseases, target the function of the Src-family tyrosine kinase Lyn. Lyn plays an important role in immune tolerance by initiating inhibitory signaling in autoreactive B cells, leading to a state of unresponsiveness or anergy. Important downstream phosphatases that mediate this inhibitory signaling are SHIP-1 and SHP-1. It is still unclear how Lyn facilitates the activation of SHIP-1 and SHP-1 in anergic B cells. Lyn phosphorylates specific motifs on inhibitory receptors (ITIM or ITSM) that enables these receptors to recruit and activate phosphatases. The aims of this proposal are to identify the Lyn-dependent inhibitory receptors required to activate SHIP-1 (Aim 1) and SHP-1 (Aim 2) in anergic B cells. We will use a novel technique, Inhibitory Receptor Trap (IRT), to identify these inhibitory receptors. IRT uses SH2 domains from SHIP-1 or SHP-1 to specifically isolate phosphorylated inhibitory receptors (indicating that the receptors are active). Isolated receptors will be identified by mass spectrometry. We will evaluate the relevance of identified receptors in anergic B cells from man and mouse. Understanding the molecular pathways by which inhibitory signaling circuits are activated in autoreactive B cells is important. Many risk alleles associated with an increased risk to develop autoimmune disease affect these inhibitory circuits. Delineating pathway relationships will allow for more accurate predictions of which risk alleles will act synergistically. This will enable us to identify individuals at heightened risk and will allow for earlier intervention and possible preventive care. Identified receptors are also potential novel targets for therapeutic intervention which may allow us to restore B cell tolerance.

项目摘要 在自身免疫性疾病的早期阶段，遗传和环境因素共同破坏免疫系统。 宽容与系统性红斑狼疮发病风险增加相关的几个风险等位基因 (SLE)和其他自身免疫性疾病，靶向Src家族酪氨酸激酶林恩的功能。林恩扮演一个 通过启动自身反应性B细胞中的抑制性信号传导，在免疫耐受中起重要作用，导致 反应迟钝或无反应性。介导这种抑制性信号传导的重要下游磷酸酶是 SHIP-1和SHP-1。目前还不清楚林恩如何促进无能B细胞中SHIP-1和SHP-1的活化。 林恩磷酸化抑制性受体（ITIM或ITSM）上的特定基序，使这些受体能够 募集并激活磷酸酶。本提案的目的是确定Lyn-dependent抑制性 在无反应性B细胞中激活SHIP-1（Aim 1）和SHP-1（Aim 2）所需的受体。我们会用一本小说 技术，抑制性受体陷阱（IRT），以确定这些抑制性受体。IRT使用来自 SHIP-1或SHP-1来特异性分离磷酸化抑制性受体（表明受体是 active）。分离的受体将通过质谱法鉴定。我们将评估已识别的 人和小鼠的无反应性B细胞中的受体。了解抑制性细胞凋亡的分子途径 信号通路在自身反应性B细胞中被激活是重要的。许多风险等位基因与 自身免疫性疾病风险的增加会影响这些抑制性回路。描绘途径 关系将允许更准确地预测哪些风险等位基因将协同作用。这将 使我们能够识别处于高风险中的个人，并允许早期干预和可能的预防 在乎已鉴定的受体也是治疗干预的潜在新靶点， 恢复B细胞耐受性。