Genetic contribution to loss of B cell anergy during development of type 1 diabetes

1 型糖尿病发展过程中 B 细胞无反应性丧失的遗传因素

• 批准号: 10178141
• 负责人: Mia Smith
• 金额: $ 13.64万
• 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: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178141
• 关键词: Acute; Advisory Committees; Affect; Affinity; Alleles; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Beta Cell; Binding; CD80 gene; CD86 gene; Cell Compartmentation; Cells; Clonal Deletion; Complex; Cytometry; Development; Development Plans; Diabetes Mellitus; Disease; Disease Resistance; Environmental Risk Factor; First Degree Relative; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; HLA Antigens; Human; Hyperglycemia; Immune Tolerance; Impairment; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; Lymphocyte; Maintenance; Memory; Mentors; Messenger RNA; Mus; Pancreas; Pathogenesis; Patients; Peripheral; Phenotype; Plasmablast; Prediabetes syndrome; Production; Proteins; Publications; Research; Resistance; Risk; Role; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Structure of beta Cell of islet; T-Lymphocyte; Technology; Training; Translating; anergy; autoreactive B cell; autoreactivity; career development; diabetic; genetic variant; genome wide association study; high risk; instructor; insulitis; lymph nodes; mouse model; new therapeutic target; novel therapeutics; prevent; receptor; response; risk variant; skills

Project Summary/Abstract This proposal for a five-year mentored research career development project focuses on elucidating the role of the type 1 diabetes (T1D) PTPN2 risk allele in loss of B cell anergy. Previously B cells bearing antigen receptors with high affinity for insulin were found only in the anergic B cell compartment of healthy individuals. Importantly, these cells leave this compartment in a proportion of first-degree relatives (FDRs), and in all autoantibody positive pre-diabetics and recent onset diabetics. Departure of these autoreactive anergic B cells in FDRs was shown to be associated with high risk T1D HLA alleles, and three high risk non-HLA alleles, including INS (rs689), PTPN2 (rs1893217), and IKZF3 (rs2872507). Of the three non-HLA risk alleles, only PTPN2 has been previously shown to be a negative regulator of signaling. However these previous studies were completed in mice, not humans, and their exact mechanism by which they contribute to development and signaling has yet to be determined. This application proposes to determine the effect of the T1D risk variant of PTPN2 in maintenance of B cell anergy. Aim 1 will explore the effect of the risk variant on the phenotype of the B cell compartment in FDRs of T1D patients and their response to stimulation. Aim 2 will explore the relationship of loss of anergic B cells with the high risk T1D genotype allele, Ptpn2, using a reductionist mouse model. The potential impact of these studies will lie in understanding how risk alleles conspire to undermine maintenance of immune tolerance to autoantigens in T1D. The candidate is an Instructor at the Barbara Davis Center for Diabetes and has brought together a diverse team of experts to serve on her advisory committee. The outlined proposal builds upon the candidate's previous research but will enable advancement of technical and analytical skills utilizing state-of-the-art technologies and will allow pursuit of new avenues of B cell research. In addition, the training and development plan is comprehensive and tailored to her needs, which will enable her to transition to independence as a highly productive veterinary scientist in the field of autoimmunity.

项目概要/摘要 这项为期五年的指导性研究职业发展项目的提案重点是阐明 1 型糖尿病 (T1D) PTPN2 风险等位基因在 B 细胞无反应性丧失中的作用。以前B细胞 仅在无反应性 B 细胞区室中发现了对胰岛素具有高亲和力的抗原受体 健康的个体。重要的是，这些细胞在一定比例的一级亲属中离开了这个区室 (FDR)，以及所有自身抗体阳性的糖尿病前期患者和新近发病的糖尿病患者。这些的出发 FDR 中的自身反应性无反应 B 细胞被证明与高风险 T1D HLA 等位基因相关，并且三个 高风险非 HLA 等位基因，包括 INS (rs689)、PTPN2 (rs1893217) 和 IKZF3 (rs2872507)。三者之中 在非 HLA 风险等位基因中，只有 PTPN2 先前已被证明是信号传导的负调节因子。然而 之前的这些研究是在老鼠身上完成的，而不是在人类身上，以及它们的确切机制 对发育和信号传导的贡献尚未确定。本申请建议确定 PTPN2 T1D 风险变异在维持 B 细胞无反应性中的作用。目标 1 将探讨风险的影响 T1D 患者 FDR 中 B 细胞区室表型的变异及其对刺激的反应。 目标 2 将探索无反应性 B 细胞损失与高风险 T1D 基因型等位基因 Ptpn2 的关系，使用 还原论小鼠模型。这些研究的潜在影响将在于了解风险等位基因如何 共同破坏 T1D 患者对自身抗原的免疫耐受的维持。 该候选人是芭芭拉·戴维斯糖尿病中心的一名讲师，并汇集了 多元化的专家团队在她的咨询委员会中任职。概述的提案建立在候选人的基础上 以前的研究，但将利用最先进的技术和分析技能来提高 技术并将允许追求 B 细胞研究的新途径。此外，培训和发展 计划是全面的，并根据她的需要量身定制，这将使她能够过渡到独立 自身免疫领域高产的兽医科学家。