Analysis of MyD88-mediated immune activation in Sjogren's syndrome pathogenesis

MyD88介导的免疫激活在干燥综合征发病机制中的分析

基本信息

批准号：
9530733
负责人：
Jill Marie Kramer
金额：
$ 35.74万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9530733
关键词：
Address Adoptive Transfer Affect Animals Antibodies Attenuated Autoantibodies Autoimmune Diseases Autoimmune Process Automobile Driving B-Lymphocytes Binding Biological Models Blood Cells Bone Marrow Cells Chronic Data Dendritic Cells Development Diagnosis Disease Early Diagnosis Etiology Event Exhibits Female Foundations Future Generations Health Hematopoietic Immune Immune System Diseases Immune System and Related Disorders Immune signaling Immune system Immunoglobulin G Immunoglobulins Inbred NOD Mice Individual Inflammation Inflammation Mediators Inflammatory Knock-out Knowledge Laboratories Ligands Lupus Lymphoma Mediating Modeling Molecular Mus Myelogenous Oral Pathogenesis Pathogenicity Pathway interactions Patients Pattern Peripheral Production Proteins Public Health Receptor Signaling Reporting Role Saliva Salivary Seminal Signal Pathway Signal Transduction Signaling Molecule Sjogren&apos s Syndrome Source Specificity Symptoms Systemic disease TLR2 gene TLR4 gene Testing Therapeutic Tissues Toll-like receptors Work autoreactive B cell biglycan curative treatments experience experimental study immune activation improved in vivo innovation lacrimal mouse model novel overexpression palliative prevent receptor expression reconstitution response salivary cell

项目摘要

Project Summary/ Abstract Sjögren's syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva production. The diagnosis of SS is challenging and patients often experience symptoms for years before they are diagnosed. Once diagnosis is achieved, no SS-specific curative treatment options are available; rather treatments for SS are palliative. Thus, there is a critical need to identify etiologic events that will facilitate earlier diagnosis of SS and mitigate or abrogate the progression of this debilitating disease. Even though the immune system drives SS, few mechanistic studies of the seminal factors responsible for SS are reported. Studies in lupus, a related autoimmune disease, demonstrated that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is critical for disease development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like receptor (TLR) signaling. Notably, TLRs are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting TLR signaling contributes to SS pathogenesis. Surprisingly, the role of MyD88 and TLR signaling has not been evaluated in depth in SS. Our central HYPOTHESES are that MyD88 expression in salivary tissue and in immune cells is crucial for SS initiation and progression and that TLR signals via MyD88 drive SS pathogenesis. Our OBJECTIVE is to evaluate the means by which MyD88-mediated signaling contributes to SS and to identify specific factors that activate TLR signaling pathways in SS. We will use a SS mouse model (NOD.B10) and our recently developed knockout strain of NOD.B10 mice that lack MyD88. These mice provide the opportunity to examine the role of MyD88 in SS. We will test our hypotheses through the following Specific Aims: (1) To determine whether MyD88 expression by hematopoietic cells is required for SS pathogenesis. These experiments will examine autoantibody production and salivary function to determine whether hematopoietic-intrinsic MyD88 expression is crucial for specific SS disease manifestations. (2) To evaluate the role of MyD88 in the generation and pathogenicity of autoantibodies in SS. These results will identify the role of MyD88 in the development of autoantibodies in SS, and will establish whether antibodies derived from MyD88-/- NOD.B10 mice have reduced pathogenicity in vivo. (3) To investigate the role of MyD88-dependent TLR2/4 activation in SS. We will determine whether signaling via TLR2/4 in salivary tissue contributes to SS in a MyD88-dependent manner. We will also overexpress a specific damage-associated molecular pattern that activates TLR2/4 in a MyD88-dependent manner to determine whether this accelerates SS. Finally, we will assess TLR2 and TLR4 blockade in SS to determine whether these attenuate disease. This study is innovative in that it will employ a novel mouse model to evaluate the role of MyD88, a key immune signaling molecule, in SS. The proposal is significant, as it will provide new knowledge regarding the role of MyD88 and TLR2/4 signaling in SS initiation and progression. This work will lay the foundation for future studies to identify therapeutics for patients with SS and other autoimmune diseases that target TLR/MyD88-related pathways.

项目摘要/摘要 Sjögren's综合征（SS）是一种自身免疫性疾病，外分泌组织受损，导致泪水丧失和唾液生产。 SS的诊断具有挑战性，患者经常经历多年的症状在诊断之前。一旦实现诊断，就不会有特定于SS的治疗方法。相反，SS治疗是姑息治疗的。那是确定将有助于促进的病因事件的迫切需要早期的SS诊断，并减轻或消除这种使人衰弱的疾病的进展。即使免疫系统驱动SS，几乎没有报告SS的第二个因素的机械研究。狼疮研究是一种相关的自身免疫性疾病，表明髓样分化因子主要反应蛋白88（MYD88）对于疾病发展至关重要。 MyD88是一个适配器分子普遍表达，对于大多数Toll样受体（TLR）信号传导所需。值得注意的是，TLR升高局部（在唾液组织中）和SS患者的外周血细胞中，表明TLR信号有助于SS 发病。令人惊讶的是，在SS中尚未对MYD88和TLR信号的作用进行评估。我们的中心假设是MyD88在唾液组织和免疫细胞中的表达对于SS起始至关重要和进展以及通过MyD88驱动SS发病机理的TLR信号。我们的目标是评估 MyD88介导的信号传导有助于SS并确定激活TLR的特定因素的方法 SS中的信号通路。我们将使用SS鼠标模型（NOD.B10）和我们最近开发的敲除菌株缺乏myd88的nod.b10小鼠。这些小鼠提供了检查MyD88在SS中的作用的机会。我们将通过以下特定目的测试我们的假设：（1）确定MyD88是否表达 SS发病机理需要造血细胞。这些实验将检查自身抗体的产生和唾液功能以确定造血内膜MyD88表达是否对特定SS疾病至关重要表现。（2）评估MyD88在SS自身抗体的产生和致病性中的作用。这些结果将确定MyD88在SS中自动抗体开发中的作用，并将确定是否是否确定是否是否源自MyD88 - / - Nod.b10小鼠的抗体在体内降低了致病性。（3）调查 SS中的MyD88依赖性TLR2/4激活。我们将确定是否在唾液组织中通过TLR2/4发出信号以MyD88依赖性方式促进SS。我们还将过表达特定的损害相关以MyD88依赖性方式激活TLR2/4的分子模式，以确定这是否加速了Ss。最后，我们将评估SS中的TLR2和TLR4阻滞，以确定这些减弱疾病。这项研究具有创新性的是，它将采用新型的鼠标模型来评估MyD88的作用，MyD88是一个关键的免疫信号传导分子，ss。该提议很重要，因为它将提供有关MyD88和的作用的新知识 SS倡议和进展中的TLR2/4信号传导。这项工作将为以后的研究奠定基础针对针对TLR/MYD88相关途径的SS和其他自身免疫性疾病的患者的治疗。