An integrated strategy to define the functional and synergistic impact of T1D causal variants

定义 T1D 因果变异的功能和协同影响的综合策略

• 批准号: 9227381
• 负责人: David J Rawlings
• 金额: $ 441.14万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227381
• 关键词: Address; Antigen Receptors; Biochemical; Biological Markers; Cells; Code; Complex; Cytokine Receptors; Data; Defect; Development; Disease; Environmental Exposure; Eragrostis; Generations; Genes; Genetic; Genetic Risk; Grant; Health; Homologous Gene; Human; IFNAR1 gene; Immune; Immune Tolerance; Individual; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-12; Islet Cell; Islets of Langerhans; Modeling; Mus; PTPN22 gene; Pathogenesis; Pathogenicity Islets; Pathway interactions; Patients; Process; Production; Proteomics; Publishing; RNA; Receptor Signaling; Research Design; Risk; Role; Sampling; Signal Transduction; Single-Gene Defect; Streptozocin; T-Cell Activation; T-Lymphocyte; TYK2; Technology; Therapeutic Agents; Variant; Viral; Work; base; biochemical tools; combinatorial; cytokine; diabetes risk; disorder risk; genetic variant; insulin dependent diabetes mellitus onset; islet; mouse model; novel marker; programs; response; risk variant; tool

ABSTRACT Type 1 diabetes (T1D) is a complex disease arising as a result of both genetic background and environmental exposures. Multiple biochemical and developmental programs have been implicated in its pathogenesis. While rare single gene defects can result in T1D, we hypothesize that T1D generally arises through a combination of synergistic defects in two or more key immune ‘programs’. Genetic variants associated with T1D can be used as a guide to understand how alterations in these programs individually and in combination contribute to the development and progression of T1D. Although multiple programs are implicated in T1D, in this grant we will focus on four coding variants, PTPN22, TYK2, SH2B3 and IFIH1. Our work and others has established that: the TID PTPN22 risk variant (PTPN22R) alters antigen receptor (AR) signaling, impacting T cell selection, development and survival; the TYK2 protective variant (TYK2P) and SH2B3 risk variant (SH2B3R) alter cytokine responses; and the IFIH1 risk variant (IFIH1R) results in enhanced IFN-1 production. In this DP3, we will address the hypothesis that PTPN22R, TYK2NP, SH2B3R variants individually and in combination contribute to the development of pathogenic islet specific T cells in T1D; and that the impact of these variants is further amplified by an enhanced Interferon response, as seen with IFIH1R, resulting in increased risk for disease development. We propose the following specific aims: Aim 1 will determine how the altered AR signaling program associated with PTPN22R leads to increased pathogenicity of islet specific effector T cells; Aim 2 will determine how SH2B3R and TYK2P contribute to alterations in the T cell activation and differentiation program in health and disease; and Aim 3 will determine whether PTPN22R synergizes with signaling programs impacted by SH2B3R, TYK2P or IFIH1R to modulate immune tolerance and T1D development. We will apply an integrated approach utilizing: primary human cells, murine models of the human risk variant, and by taking advantage of cutting edge gene editing and proteomics technologies. This approach will allow us to comprehensively interrogate the functional implications of these specific genes and, how the signaling programs that they modulate, function in concert to contribute to TID. Notably, we have found that the altered programs driven by T1D risk variants often mimic those observed in disease, even in patients lacking the specific risk variants we model. Thus, studies of specific genetic risk variants and their functional implications are broadly applicable to understanding the pathogenesis of T1D and will inform the development of new biomarkers and therapeutic agents to treat type 1 diabetes.

抽象的 1型糖尿病（T1D）是一种复杂的疾病，是遗传背景和环境因素共同作用的结果。 曝光。多种生化和发育程序与其发病机制有关。尽管 罕见的单基因缺陷可导致 1 型糖尿病，我们假设 1 型糖尿病通常是由以下因素的组合引起的： 两个或多个关键免疫“程序”的协同缺陷。可以使用与 T1D 相关的遗传变异 作为理解这些程序的单独和组合的改变如何有助于 T1D 的发生和进展。尽管 T1D 涉及多个项目，但在这笔赠款中，我们将 重点关注四种编码变体：PTPN22、TYK2、SH2B3 和 IFIH1。我们和其他人的工作已经证实： TID PTPN22 风险变异 (PTPN22R) 改变抗原受体 (AR) 信号传导，影响 T 细胞选择， 发展与生存； TYK2 保护性变异 (TYK2P) 和 SH2B3 风险变异 (SH2B3R) 改变细胞因子 回应； IFIH1 风险变异 (IFIH1R) 会导致 IFN-1 产生增强。在这个 DP3 中，我们将 解决了以下假设：PTPN22R、TYK2NP、SH2B3R 变体单独和组合有助于 T1D 中致病性胰岛特异性 T 细胞的发育；这些变体的影响进一步 如 IFIH1R 所示，干扰素反应增强，从而导致疾病风险增加 发展。我们提出以下具体目标： 目标 1 将确定如何改变 AR 信号 与 PTPN22R 相关的程序导致胰岛特异性效应 T 细胞的致病性增加；目标2将 确定 SH2B3R 和 TYK2P 如何促进 T 细胞激活和分化程序的改变 在健康和疾病方面；目标3将确定PTPN22R是否与信令程序协同作用 受 SH2B3R、TYK2P 或 IFIH1R 影响，调节免疫耐受和 T1D 发展。我们将申请一个 综合方法利用：原代人类细胞、人类风险变异的小鼠模型，并通过采取 尖端基因编辑和蛋白质组学技术的优势。这种方法将使我们能够 全面询问这些特定基因的功能含义，以及信号传导如何 他们调节的程序协同运作，为 TID 做出贡献。值得注意的是，我们发现改变后的 由 T1D 风险变异驱动的项目常常模仿在疾病中观察到的项目，即使是在缺乏 T1D 风险变异的患者中 我们建模的特定风险变体。因此，对特定遗传风险变异及其功能意义的研究 广泛适用于了解 T1D 的发病机制，并将为新疗法的开发提供信息 治疗 1 型糖尿病的生物标志物和治疗药物。