Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis

MyD88介导的干燥综合征发病机制中的免疫激活分析

• 批准号: 10363733
• 负责人: Jill Marie Kramer
• 金额: $ 36.82万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363733
• 关键词: Address; Affect; Autoimmune; Autoimmune Diseases; Automobile Driving; B-Cell Activation; B-Lymphocytes; Biological Models; Biological Response Modifiers; Blood Cells; Cell Nucleus; Cells; Chronic; Cytokine Network Pathway; Data; Development; Diagnosis; Disease; Early Diagnosis; Endosomes; Etiology; Event; Exhibits; Exocrine Glands; Family; Family member; Health; Hematopoietic; Immune; Immune System Diseases; Immune mediated destruction; Individual; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-1 Receptors; Knock-out; Laboratories; Lacrimal gland structure; Liquid substance; Lupus; Mediating; Mediator of activation protein; Modeling; Mus; Myelogenous; Oral; Pathogenesis; Pathway interactions; Patients; Peripheral; Proteins; Public Health; Reporting; Research; Rest; Role; Saliva; Salivary; Salivary Gland Tissue; Salivary Glands; Sampling; Seminal; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Symptoms; Systemic disease; TLR7 gene; Testing; Therapeutic; Tissues; Toll-like receptors; cell type; conditional knockout; curative treatments; cytokine; immune activation; improved; innovation; insight; lacrimal; member; morphogens; mouse model; novel; palliative; peripheral blood; receptor; response; systemic inflammatory response; therapeutic development

Project Summary Sjögren’s syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva. Primary SS (pSS) affects salivary and lacrimal tissue and results in many serious systemic disease manifestations. 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 development of therapeutics that mitigate the progression of this debilitating disease. Studies in our laboratory revealed that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is essential for pSS development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like receptor (TLR) and IL-1 receptor (IL-1R) family member signaling. Notably, TLRs and IL-1R family members are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting these receptors contribute to SS. Our central hypotheses are that (i) tissue-specific MyD88 expression dictates distinct pSS disease manifestations and that (ii) activation of MyD88-dependent signaling networks drives pSS pathogenesis. Our objectives are to identify the tissue-specific contributions of MyD88 and to determine the MyD88-mediated signaling networks that govern pSS disease pathogenesis. We will employ a pSS mouse model (NOD.B10) and a conditional knockout strain of NOD.B10 mice developed in our laboratory that lacks expression of MyD88 in the hematopoietic compartment (immune cells) specifically. These mice provide a unique model system to examine the role of MyD88 in pSS directly. The rationale for this proposal rests on the fact that activation of MyD88-mediated signaling pathways contributes to many autoimmune diseases. Both salivary tissue and immune cells express receptors that promote inflammation via MyD88, such as TLRs and IL-1R family members. Our studies in pSS mice deficient in MyD88 demonstrate that MyD88 is crucial for pSS pathogenesis; however, the specific cell types that express MyD88 in disease and the MyD88-dependent signaling pathways that are activated in pSS are incompletely understood. We will test our hypotheses by completion of three specific aims: (1) Identify immune cell-specific contributions of MyD88 to pSS pathogenesis, (2) Evaluate MyD88-dependent IL-36-related cytokines in pSS, and (3) Assess the role of the MyD88-dependent endosomal TLRs, TLR7 and TLR9, in pSS. This study is innovative because it will uncover new mechanisms related to the role of MyD88-dependent signaling networks in pSS and will identify specific cell types that mediate distinct pSS disease manifestations. Targeted blockade of MyD88-dependent TLR and IL-1R family member signaling pathways represents an innovative therapeutic approach for the treatment of pSS. This proposal is significant because it will reveal new mechanisms that govern chronic inflammation in pSS. Insights obtained from the proposed studies will reveal novel pathways that can be targeted to treat pSS and other autoimmune diseases.

项目摘要 Sjögren综合征（SS）是一种自身免疫性疾病，外分泌组织受损，导致损失 眼泪和唾液。主要SS（PSS）影响唾液和泪组织，并导致许多严重的全身性 疾病表现。一旦实现诊断，就没有SS特异性的治疗方法。相当 SS治疗是姑息治疗的。这是肯定需要确定将有助于早期促进的病因事件。 SS的诊断和理论的发展，以减轻这种使人衰弱的疾病的发展。研究 在我们的实验室中表明，髓样分化因子主要反应蛋白88（MyD88）对于 PSS开发。 MyD88是一个适配器分子，它无处不在，大多数Toll样子都需要 受体（TLR）和IL-1受体（IL-1R）家族成员信号传导。值得注意的是，TLR和IL-1R家庭成员是 SS患者的局部升高（在唾液组织中）和外周血细胞中，这表明这些受体有助于 到SS。我们的中心假设是（i）组织特异性myd88表达决定了不同的PSS病 表现以及（ii）MyD88依赖性信号网络的激活驱动PSS发病机理。我们的 目标是确定MyD88的组织特异性贡献，并确定MyD88介导的信号传导 控制PSS疾病发病机理的网络。我们将采用PSS鼠标模型（NOD.B10）和条件 在我们的实验室中开发的点头小鼠的敲除菌株，该小鼠在造血中缺乏Myd88的表达 特定的腔室（免疫细胞）。这些小鼠提供了一个独特的模型系统来检查MyD88的作用 直接在PSS中。该提案的基本原理取决于以下事实：MyD88介导的信号通路的激活 导致许多自身免疫性疾病。唾液组织和免疫细胞都表达促进的受体 MyD88的炎症，例如TLR和IL-1R家庭成员。我们在MyD88缺乏PSS小鼠的研究 证明MyD88对于PSS发病机理至关重要。但是，在 在PSS中激活的疾病和MyD88依赖性信号通路尚不完全了解。我们 将通过完成三个特定目的来检验我们的假设：（1）确定MYD88的免疫小球特异性贡献 对于PSS发病机理，（2）评估PSS中与MyD88依赖性IL-36相关细胞因子，并且（3）评估 pss中的MyD88依赖性内体TLRS TLR7和TLR9。这项研究具有创新性，因为它将发现新的 与MyD88依赖性信号网络在PSS中的作用相关的机制，并将识别特定的细胞类型 媒体不同的PSS疾病表现。针对MyD88依赖性TLR和IL-1R家族的目标封锁 成员信号通路代表一种用于治疗PSS的创新治疗方法。这个建议 之所以重要，是因为它将揭示支配PSS慢性炎症的新机制。从获得的见解 拟议的研究将揭示可针对治疗PSS和其他自身免疫性疾病的新途径。