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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

基本信息

批准号：
10187517
负责人：
Andrew Getahun
金额：
$ 18.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-09 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187517
关键词：
Adaptor Signaling Protein Affect Autoantigens Autoimmune Diseases B-Cell Antigen Receptor 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 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

项目摘要

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.

项目概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。几种与系统性红斑狼疮风险增加相关的风险等位基因 (SLE) 和其他自身免疫性疾病均以 Src 家族酪氨酸激酶 Lyn 的功能为目标。林扮演一个通过在自身反应性 B 细胞中启动抑制信号传导，导致免疫耐受状态中发挥重要作用反应迟钝或无反应。介导这种抑制信号传导的重要下游磷酸酶是 SHIP-1 和 SHP-1。目前尚不清楚 Lyn 如何促进无能 B 细胞中 SHIP-1 和 SHP-1 的激活。 Lyn 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。该提案的目的是确定 Lyn 依赖性抑制激活无能 B 细胞中的 SHIP-1 (Aim 1) 和 SHP-1 (Aim 2) 所需的受体。我们将用小说抑制性受体陷阱（IRT）技术来识别这些抑制性受体。 IRT 使用 SH2 域 SHIP-1 或 SHP-1 特异性分离磷酸化抑制性受体（表明这些受体是积极的）。分离的受体将通过质谱法进行鉴定。我们将评估已识别的相关性人和小鼠的无反应性 B 细胞中的受体。了解抑制的分子途径信号通路的激活在自身反应性 B 细胞中非常重要。许多风险等位基因与患自身免疫性疾病的风险增加会影响这些抑制回路。描绘路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高风险个人，并能够及早进行干预和可能的预防关心。已识别的受体也是治疗干预的潜在新靶标，这可能使我们能够恢复B细胞耐受性。