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.

项目概要 干燥综合征 (SS) 是一种自身免疫性疾病，其中外分泌组织受损，导致丧失 眼泪和唾液。原发性 SS (pSS) 影响唾液和泪腺组织，并导致许多严重的全身性疾病 疾病表现。一旦确诊，就没有针对 SS 的治疗方案；相当 SS 的治疗是姑息性的。因此，迫切需要确定病因事件，以促进早期发现 SS 的诊断和开发缓解这种使人衰弱的疾病进展的疗法。研究 我们的实验室发现，骨髓分化因子初级反应蛋白 88 (MyD88) 对于 pSS 开发。 MyD88 是一种普遍表达的接头分子，是大多数 Toll 样蛋白所必需的 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 家族成员是 SS 患者的局部（唾液组织）和外周血细胞中升高，表明这些受体有助于 到党卫军。我们的中心假设是 (i) 组织特异性 MyD88 表达决定不同的 pSS 疾病 (ii) MyD88 依赖性信号网络的激活驱动 pSS 发病机制。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 疾病发病机制的网络。我们将采用 pSS 小鼠模型 (NOD.B10) 和条件 我们实验室开发的 NOD.B10 小鼠敲除品系，其造血系统中缺乏 MyD88 的表达 特别是隔室（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。该提议的基本原理在于 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受体，促进 通过 MyD88 产生炎症，例如 TLR 和 IL-1R 家族成员。我们对 MyD88 缺陷的 pSS 小鼠的研究 证明 MyD88 对于 pSS 发病机制至关重要；然而，表达 MyD88 的特定细胞类型 疾病和 pSS 中激活的 MyD88 依赖性信号通路尚不完全清楚。我们 将通过完成三个具体目标来检验我们的假设：(1) 识别 MyD88 的免疫细胞特异性贡献 pSS 发病机制，(2) 评估 pSS 中 MyD88 依赖性 IL-36 相关细胞因子，以及 (3) 评估 pSS 中 MyD88 依赖性 IL-36 相关细胞因子的作用 pSS 中 MyD88 依赖性内体 TLR、TLR7 和 TLR9。这项研究具有创新性，因为它将发现新的 与 pSS 中 MyD88 依赖性信号网络的作用相关的机制，并将识别特定的细胞类型 介导不同的 pSS 疾病表现。靶向阻断 MyD88 依赖性 TLR 和 IL-1R 家族 成员信号通路代表了治疗 pSS 的创新治疗方法。这个提议 意义重大，因为它将揭示控制 pSS 慢性炎症的新机制。获得的见解 拟议的研究将揭示可用于治疗 pSS 和其他自身免疫性疾病的新途径。