Bruton's Tyrosine Kinase and Immune Tolerance in Type 1 Diabetes

布鲁顿酪氨酸激酶和 1 型糖尿病的免疫耐受

基本信息

批准号：
8776292
负责人：
Peggy L Kendall
金额：
$ 32.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-27 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776292
关键词：
Address Adoptive Transfer Agammaglobulinaemia tyrosine kinase Amino Acids Antigen Presentation Antigens Autoantibodies Autoantigens Autoimmune Diabetes B cell repertoire B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Binding Biological Assay Cell physiology Cells Clinical Complement 3d Receptors Complex Dependence Development Diabetes Mellitus Disease Disease Progression Effectiveness Employee Strikes Event Goals Health Immune Tolerance Immunoglobulin G Inbred NOD Mice Individual Insulin Insulin-Dependent Diabetes Mellitus Intervention Islet Cell Knock-out Lead Link Mature B-Lymphocyte Mediating Modeling Molecular Mus Outcome Phosphotransferases Play Process Property Receptor Signaling Receptors, Antigen, B-Cell Role Signal Pathway Signal Transduction Signaling Molecule Specificity Staging System T-Lymphocyte Testing Therapeutic Intervention Transgenic Mice Transgenic Model Transgenic Organisms Tyrosine Kinase Domain Tyrosine Kinase Inhibitor adapter protein antigen binding autoreactive B cell autoreactivity base islet mouse model novel prevent reconstitution research study response small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of islet 2 cells. B lymphocytes (B cells) play a critical role in disease development, probably via antigen-presentation to pathogenic T cells. B cell contribution to the development of diabetes depends upon multiple factors, including loss of tolerance to self antigen. This tolerance is mediated by cellular responses to antigen-binding via the B cell receptor (BCR). Bruton's tyrosine kinase (BTK) is a central component of the BCR-triggered signaling pathway. Understanding cell signaling components underlying B cell-driven diabetes development will advance the field toward specific targeting of pathogenic B cells. We have introgressed btk-deficiency onto the nonobese diabetic (NOD) mouse model of T1D, and found that this results in significant protection against the development of diabetes. In addition, btk-deficiency interferes with B cell related breaches of immune tolerance, as evidenced by the loss of insulin-specific IgG autoantibodies in wild type NOD mice, and reduction of insulin-binding B cells in a transgenic anti-insulin BCR model. The specific hypothesis underlying this proposal is that BTK-mediated propagation of BCR signals contributes to 1) selection and survival of autoreactive B lymphocytes, and 2) disease- promoting functional properties of these B cells. To understand the mechanisms of action of BTK in breaking B lymphocyte tolerance and promoting disease in autoimmune diabetes, we propose to: 1) discover how BTK participates in the selection and retention of autoreactive B lymphocytes, using use new tools that include a conditional, B cell-specific BTK knockout model and small molecule BTK- inhibitors, 2) determine which domains of the BTK molecule are responsible for autoreactive B lymphocyte selection and function, by systematically restoring independent components responsible for the kinase and linking functions, and 3) investigate the mechanisms of btk-deficiency in preventing T1D by examining effects on B cell subsets, antigen-presenting outcomes, and regulatory parameters. This project has direct clinical importance in understanding how BCR-signaling supports the selection, survival and function of autoreactive B cells in T1D, as a necessary step in developing therapeutic interventions.

描述（由申请人提供）：1型糖尿病（T1D）是由一系列复杂的事件级联导致的，这些事件破坏了免疫耐受性并在胰岛2细胞的破坏中达到顶峰。 B淋巴细胞（B细胞）在疾病发育中起着至关重要的作用，可能是通过对致病性T细胞的抗原呈递的。 B细胞对糖尿病发育的贡献取决于多种因素，包括失去对自抗原的耐受性。这种耐受性是通过通过B细胞受体（BCR）对抗原结合的细胞反应介导的。 Bruton的酪氨酸激酶（BTK）是BCR触发信号通路的中心成分。了解B细胞驱动的糖尿病发育基础的细胞信号传导成分将使该领域朝着病原B细胞的特定靶向。我们对T1D的非肥胖糖尿病（NOD）小鼠模型进行了渗透的BTK缺乏症，并发现这会导致对糖尿病发展的显着保护。此外，BTK缺乏症会干扰B细胞相关的免疫耐受性违规行为，这是由野生型NOD小鼠中胰岛素特异性IgG自身抗体的丧失所证明的，而在转基因抗胰岛素BCR模型中降低了胰岛素结合B细胞。该提案的基本假设是BTK介导的BCR信号的传播有助于1）自动反应性B淋巴细胞的选择和存活，以及2）促进这些B细胞的疾病 - 促进这些B细胞的功能特性。 To understand the mechanisms of action of BTK in breaking B lymphocyte tolerance and promoting disease in autoimmune diabetes, we propose to: 1) discover how BTK participates in the selection and retention of autoreactive B lymphocytes, using use new tools that include a conditional, B cell-specific BTK knockout model and small molecule BTK- inhibitors, 2) determine which domains of the BTK分子通过系统地恢复负责激酶和链接功能的独立组件以及3）调查BTK缺陷在预防T1D方面的机制，通过检查B细胞子集对BTK细胞子集的影响，抗原抗原 - 特性抗原及调节参数来预防T1D的机制。该项目在理解BCR信号如何支持T1D中自动反应性B细胞的选择，生存和功能方面具有直接的临床重要性，这是开发治疗干预措施的必要步骤。