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: 10599234
• 负责人: Jill Marie Kramer
• 金额: $ 37.17万
• 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/10599234
• 关键词: Affect; Agonist; Autoimmune; Autoimmune Diseases; Autoimmunity; 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; Immune system; Individual; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-1 Receptors; Knock-out; Laboratories; Lacrimal gland structure; Liquid substance; Lupus; Mediating; Mediator; Modeling; Mus; Myelogenous; Oral; Pathogenesis; Pathway interactions; Patients; 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 干燥综合征(SS)是一种自身免疫性疾病，外分泌组织受损，导致丢失 泪水和唾液。原发性SS(PSS)累及唾液和泪腺组织，导致许多严重的系统性疾病 疾病表现。一旦获得诊断，就没有针对SS的治疗方案可用；相反 SS的治疗是姑息性的。因此，迫切需要识别有助于更早发生的病因事件。 SS的诊断和治疗方法的发展，以减缓这种衰弱疾病的进展。研究 我们实验室发现，髓系分化因子初级反应蛋白88(MyD88)是 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)和白介素1受体(IL-1R)家族成员信号传导。值得注意的是，TLRs和IL-1R家族成员是 SS患者局部(唾液组织)和外周血细胞的升高，表明这些受体参与了 致党卫军。我们的中心假设是：(I)组织特异性MyD88的表达决定了不同的PSS疾病 (2)依赖于MyD88的信号网络的激活推动了PSS的发病。我们的 目的是确定MyD88的组织特异性贡献，并确定MyD88介导的信号转导 控制PSS疾病发病机制的网络。我们将采用PSS小鼠模型(NOD.B10)和条件性 本实验室培育的在造血细胞中缺乏MyD88表达的NOD.B10基因敲除小鼠 特定的隔室(免疫细胞)。这些小鼠提供了一种独特的模型系统来检测MyD88的作用 直接在PSS中。这一建议的基础是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 通过MyD88的炎症，如TLRs和IL-1R家族成员。我们对MyD88缺陷的PSS小鼠的研究 证明MyD88在PSS发病机制中起关键作用；然而，在PSS中表达MyD88的特定细胞类型 疾病和依赖于MyD88的信号通路在PSS中被激活，目前还不完全清楚。我们 我将通过完成三个具体目标来验证我们的假设：(1)确定MyD88的免疫细胞特异性贡献 对于PSS的发病机制，(2)评估依赖MyD88的IL-36相关细胞因子在PSS中的作用；(3)评估MyD88依赖的IL-36在PSS中的作用 PSS中依赖MyD88的内体TLRs，TLR7和TLR9。这项研究具有创新性，因为它将发现新的 与依赖MyD88的信号网络在PSS中的作用相关的机制，并将识别特定的细胞类型 介导了不同的PSS疾病表现。靶向阻断依赖MyD88的TLR和IL-1R家族 成员信号通路代表了治疗PSS的一种创新的治疗方法。这项建议 意义重大，因为它将揭示治理PSS慢性炎症的新机制。从以下方面获得的见解 拟议的研究将揭示可以靶向治疗PSS和其他自身免疫性疾病的新途径。