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: 10431828
• 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/10431828
• 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.

项目总结/摘要 这项为期五年的研究职业发展项目的建议侧重于阐明 1型糖尿病（T1 D）PTPN 2危险等位基因在B细胞失能中的作用以前的B细胞 对胰岛素具有高亲和力的抗原受体仅在无反应性的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区室 （FDR），并在所有自身抗体阳性的糖尿病前期和近期发病的糖尿病患者。离开这些 研究表明，FDR中的自身反应性无能B细胞与高风险T1 D HLA等位基因相关，并且有三种 高危非HLA等位基因，包括INS（rs689）、PTPN 2（rs 1893217）和IKZF 3（rs 2872507）。三 在非HLA风险等位基因中，只有PTPN 2先前已被证明是信号传导的负调节剂。然而 这些先前的研究是在小鼠中完成的，而不是在人类中完成的，它们的确切机制是， 有助于发展和信号尚未确定。本申请建议确定 PTPN 2的T1 D风险变体在维持B细胞无反应性中的作用。目标1将探讨风险的影响 T1 D患者FDR中B细胞区室的表型变异及其对刺激的反应。 目的2将探讨无反应性B细胞丢失与高危T1 D基因型等位基因Ptpn 2的关系， 一个简化的老鼠模型。这些研究的潜在影响将在于理解风险等位基因如何 共同破坏T1 D中对自身抗原的免疫耐受性的维持。 候选人是芭芭拉戴维斯糖尿病中心的讲师， 不同的专家团队在她的咨询委员会任职。概述的建议建立在候选人的基础上， 以前的研究，但将能够利用最先进的技术和分析技能的进步 技术，并将允许追求B细胞研究的新途径。此外，培训和发展 该计划是全面的，符合她的需要，这将使她能够过渡到独立， 在自身免疫领域卓有成效的兽医科学家。