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)、格雷夫斯病 (GD) 和桥本甲状腺炎 (HT) 是最常见的自身免疫性疾病，由于其机制尚不完全清楚，因此对 AITD 进行对症治疗（HT 中的激素替代或 GD 中的激素抑制）。）因此，患者往往难以管理，因此需要针对引起 AITD 的自身免疫机制的新疗法。AITD 是由易感基因和环境相互作用引起的复杂疾病。我们和其他人已经绘制并确认了多种 AITD 基因，包括甲状腺球蛋白 (Tg)。我们还表明，病毒感染期间产生的干扰素 α (IFNα) 是触发 AITD 的关键细胞因子。我们的重点是诱发 AITD 的遗传机制（目标 1）、AITD 的环境触发因素（目标 2）以及 AITD 的药物触发因素。 AITD（目标 3）。在目标 1 中，我们将测试与 AITD 相关的 Tg 中的错义 SNP 通过增加 Tg 错误折叠并增强其降解为免疫原性肽而诱发 AITD 的假设。我们的研究中，自身免疫性甲状腺炎是通过非复制腺病毒载体中的人 Tg cDNA 免疫诱导的，该模型使我们能够测试不同 Tg 的效果。 SNP 对 AITD 敏感或具有保护作用，并评估这些 Tg 变体触发 AITD 的体内机制。在目标 2 中，我们将测试 IFNα 通过将 Tg 自噬降解为免疫原性肽来触发 AITD 的假设。细胞系和甲状腺过度表达 IFNα 的小鼠模型，以确定 Tg 降解的自噬-溶酶体途径；我们还将测试小鼠中生成的 Tg 肽的免疫原性；该目标将定义一种通过 IFNα 介导的自身抗原降解触发自身免疫的新统一机制。在目标 3 中，我们将测试甲状腺细胞上表达的程序性死亡配体 1 (PD-L1) 具有内在活性的假设。在炎症过程中保护它们免受细胞内应激，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引发甲状腺炎。我们开发了 ICI 甲状腺炎小鼠模型，以剖析 PD-L1 阻断在体内引发甲状腺炎的机制，这一目标将明确 ICI 诱导的甲状腺炎的机制以及甲状腺 PD-L1 在 AITD 中的作用。该提案中的研究将有助于推进我们的长期目标，即设计针对自身免疫性甲状腺疾病的基于机制的靶向疗法。