Analyzing genetic and environmental molecular mechanisms causing autoimmune thyroid diseases

分析导致自身免疫性甲状腺疾病的遗传和环境分子机制

基本信息

批准号：
10693959
负责人：
MIHAELA STEFAN-LIFSHITZ
金额：
$ 42万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693959
关键词：
Acceleration Adenovirus Vector Alprostadil Apoptosis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Autophagocytosis Binding Biological Assay Biotin Cathepsins Cell Line Cells Co-Immunoprecipitations Complementary DNA Complex Development Disease Electron Microscopy Environmental Risk Factor Genes Genetic Goals Graves&apos Disease Hashimoto Disease Hormones Human Immune Immune checkpoint inhibitor Immunization Inflammation Interferon alpha Interferons Label Lead Ligation Maps Mass Spectrum Analysis Mediating Mediator Modeling Molecular Mus Mutate Mutation Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Post-Translational Protein Processing Predisposition Process Proteins Role Signal Transduction Stress Susceptibility Gene T-Lymphocyte T-Lymphocyte Epitopes Techniques Testing Thyroglobulin Thyroid Gland Thyroiditis Time Toxic effect Translating Up-Regulation Variant Viral Virus Diseases anti-PD-L1 autoimmune thyroid disease cytokine design endoplasmic reticulum stress experience immunogenic immunogenicity in vivo mouse model multidisciplinary mutant new therapeutic target novel novel therapeutics overexpression prevent programmed cell death ligand 1 programmed cell death protein 1 protective effect response

项目摘要

The autoimmune thyroid diseases (AITD), Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are the most common autoimmune diseases. Because their mechanisms are not fully understood, AITD are treated symptomatically (hormone replacement in HT or hormone suppression in GD) and as a result, patients are often difficult to manage. Therefore, new therapies are needed that target the autoimmune mechanisms causing AITD. AITD are complex diseases caused by interactions between susceptibility genes and environmental triggers. We and others have mapped & confirmed several AITD genes, including thyroglobulin (Tg). We have also shown that interferon alpha (IFNα), produced during viral infections, is the key cytokine triggering AITD. The current proposal aims to dissect the genetic and environmental mechanisms causing AITD in order to target them with novel therapies. Our focus is on genetic mechanisms predisposing to AITD (Aim 1), environmental triggers of AITD (Aim 2), and medication triggers of AITD (Aim 3). In Aim 1 we will test the hypothesis that missense SNPs in Tg that are associated with AITD predispose to AITD by increasing Tg misfolding and enhancing its degradation into immunogenic peptides. We will use a novel muse model of AITD developed by us, in which autoimmune thyroiditis is induced by immunization with human Tg cDNA in a non-replicating Adenovirus vector. This model enables us to test the effects of different Tg SNPs shown to be susceptible or protective for AITD, and to assess in vivo mechanisms by which these Tg variants trigger AITD. In Aim 2 we will test the hypothesis that IFNα triggers AITD by engaging the autophagic degradation of Tg into immunogenic peptides. We will use cell lines and a mouse model with thyroid over-expression of IFNα to define the autophagy-lysosomal pathways of Tg degradation; we will also test the immunogenicity of the generated Tg peptides in mouse models and PBMC’s from AITD patients. This aim will define a new unifying mechanism for triggering autoimmunity by IFNα-mediated autoantigen degradation. In Aim 3 we will test the hypothesis that Programmed death-ligand 1 (PD-L1) expressed on thyrocytes has intrinsic activity protecting them from intracellular stress during inflammation, and that Immune Checkpoint Inhibitors (ICI’s) trigger thyroiditis by blocking these intrinsic protective effects of PD-L1. We will use a new mouse model of ICI-thyroiditis we developed to dissect the mechanisms by which PD-L1 blockade triggers thyroiditis in vivo. This aim will define the mechanisms of ICI-induced thyroiditis as well as the role of thyroidal PD-L1 in AITD. Collectively, the studies in this proposal will help advance our long-term goal, to design targeted mechanism-based therapies for autoimmune thyroid diseases.

自身免疫性甲状腺疾病（AITD），GRAVES病（GD）和桥本甲状腺炎（HT）是最常见的自身免疫性疾病。由于其机制尚未完全理解，因此AITD经过症状治疗（HT中的激素替代或GD中的Horsene抑制），因此，患者通常难以管理。因此，需要新的疗法，以靶向引起AITD的自身免疫机制。 AITD是由易感基因与环境触发因素之间的相互作用引起的复杂疾病。我们和其他人已经映射并确认了几个AITD基因，包括甲状腺球蛋白（TG）。我们还表明，在病毒感染过程中产生的干扰素α（IFNα）是触发AITD的关键细胞因子。当前的提案旨在剖析引起AITD的遗传和环境机制，以便使用新颖的疗法将其靶向。我们的重点是易于AITD（AIM 1），AITD的环境触发器（AIM 2）和AITD的药物触发器（AIM 3）的遗传机制。在AIM 1中，我们将测试以下假设：TG中的错义SNP与AITD易感性相关的AITD通过增加TG失误并增强其降解为免疫原性Petides。我们将使用美国开发的AITD的新型Muse模型，其中自身免疫性甲状腺炎是通过在非复制腺病毒载体中用人TG cDNA进行免疫化诱导的。该模型使我们能够测试显示出对AITD易感或保护的不同TG SNP的影响，并评估这些TG变体触发AITD的体内机制。在AIM 2中，我们将测试以下假设：IFNα通过将TG自噬降解为免疫原性肽来触发AITD。我们将使用IFNα的甲状腺过表达的细胞系和小鼠模型来定义TG降解的自噬溶质体途径；我们还将测试来自AITD患者的小鼠模型和PBMC中产生的TG肽的免疫原性。这个目标将定义一种新的统一机制，用于通过IFNα介导的自身抗原降解来触发自身免疫。在AIM 3中，我们将检验以下假设：在甲状腺细胞上表达的程序性死亡 - 辅助仪1（PD-L1）具有固有活性，可保护它们在炎症过程中免受细胞内应激的影响，并且免疫检查点抑制剂（ICI）通过阻断Pd-L1的这些内在保护作用来触发甲状腺炎。我们将使用一种新的小鼠甲状腺炎模型，以剖析PD-L1封锁在体内触发甲状腺炎的机制。该目标将定义ICI诱发的甲状腺炎的机制以及甲状腺PD-L1在AITD中的作用。总的来说，该提案中的研究将有助于促进我们的长期目标，以设计基于机制的自身免疫性甲状腺疾病的疗法。