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: 10055413
• 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/10055413
• 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; To autoantigen; 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 这份为期五年的指导性研究职业发展项目的提案侧重于阐明 1型糖尿病(T1D)PTPN2风险等位基因在B细胞无能丧失中的作用。以前的B细胞 与胰岛素有高亲和力的承载抗原受体仅在无能B细胞室中发现 健康的个体。重要的是，这些细胞以一级亲属的比例离开这个隔室。 (FDRs)，在所有自身抗体阳性的糖尿病前期患者和新发糖尿病患者中。这些人的离开 FDRS中的自身反应性无能B细胞被证明与高危的T1D HLA等位基因有关，还有三个 高危非HLA等位基因，包括INS(Rs689)、PTPN2(Rs1893217)和IKZF3(Rs2872507)。三个人中的一个 对于非人类白细胞抗原风险等位基因，以前只有PTPN2被证明是信号的负调节因子。然而， 这些先前的研究是在老鼠身上完成的，而不是在人类身上完成的，以及它们的确切机制 对发展的贡献和信号还有待确定。此应用程序建议确定 PTPN2T1D风险变异体在维持B细胞无能中的作用目标1将探讨风险的影响 T1D患者FDRs的B细胞室表型变异及其对刺激的反应 目的2将探讨无能B细胞丢失与高危T1D基因型等位基因PTPN2的关系 一个简化主义的老鼠模型。这些研究的潜在影响将在于理解风险等位基因如何 合谋破坏对T1D自身抗原的免疫耐受性的维持。 这位候选人是芭芭拉·戴维斯糖尿病中心的一名讲师，她汇集了一位 在她的咨询委员会中担任不同的专家团队。概述的提案建立在候选人的基础上 以前的研究，但将使技术和分析技能的进步利用最先进的技术 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做，这将使她能够过渡到独立作为一名 在自身免疫领域高产的兽医科学家。