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.

项目摘要/摘要 这项为期五年的研究职业发展项目的提案着重于阐明 1型糖尿病（T1D）PTPN2等位基因损失B细胞消极的作用。以前B细胞 仅在厌食的B细胞室中发现具有高亲和力的抗原受体 健康的个体。重要的是，这些细胞以一级亲戚的比例离开该隔室 （FDR），以及在所有自身抗体阳性前糖尿病患者和近期糖尿病患者中。这些离开 FDR中的自动反应性Anergic B细胞被证明与高风险T1D HLA等位基因相关，三个 高风险非HLA等位基因，包括INS（RS689），PTPN2（RS1893217）和IKZF3（RS2872507）。三个 非HLA风险等位基因，以前仅显示PTPN2是信号传导的负调节剂。然而 这些先前的研究是在小鼠而不是人类中完成的，它们的确切机制 有助于开发和信号传导尚未确定。本申请建议确定 PTPN2 T1D风险变体在维持B细胞消极的影响。 AIM 1将探索风险的影响 T1D患者FDR的B细胞室表型的变体及其对刺激的反应。 AIM 2将探索使用过度B细胞的丧失与高风险T1D基因型等位基因PTPN2的关系 简还原鼠标模型。这些研究的潜在影响将在于了解如何风险等位基因 共谋破坏T1D中对自动抗原的免疫耐受性的维持。 候选人是芭芭拉·戴维斯（Barbara Davis）糖尿病中心的讲师，并将 多样化的专家团队将在她的咨询委员会任职。概述的提案建立在候选人的 先前的研究，但将实现利用最先进的技术和分析技能的发展 技术，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，适合她的需求，这将使她能够过渡到独立性 自身免疫领域的高产兽医科学家。