Targeting Endogenous Mesenchymal Stromal Cells with Ruxolitinib to Treat Sialadenitis in Sjogren's Syndrome

用鲁索替尼靶向内源性间充质基质细胞治疗干燥综合征的唾液腺炎

基本信息

批准号：
10524424
负责人：
Sara Mccoy
金额：
$ 15.55万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524424
关键词：
Adipose tissue Adult Affect Anti-Inflammatory Agents Antigen-Presenting Cells Antiinflammatory Effect Autoantibodies B-Lymphocytes Biological Bone Marrow Cell Therapy Cells ChIP-seq Clinical Trials Coculture Techniques Data Disease Dryness Equilibrium Evaluation FDA approved Flow Cytometry Future Gene Expression Generations Genetic Transcription Gland Goals Health Histocompatibility Human Immune system Immunobiology In Vitro Inflammation Inflammatory Innovative Therapy Interferon-alpha Interferons JAK1 gene JAK2 gene Janus kinase Knock-out Knowledge Lacrimal gland structure Lymphocytic Infiltrate Measures Mediating Mission Modality Morbidity - disease rate Mus National Institute of Dental and Craniofacial Research Oral Oral Characters Oral health Organ Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Pilot Projects Play Population Prevalence Production Property Regenerative capacity Regulatory T-Lymphocyte Research Rheumatoid Arthritis Role STAT1 gene Saliva Salivary Salivary Gland Diseases Salivary Glands Sialadenitis Signal Transduction Sjogren&apos s Syndrome Sodium Glutamate Synovitis T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Thinking Tissues Tryptophan 2,3 Dioxygenase United States National Institutes of Health Up-Regulation base cell type chromatin immunoprecipitation cost cytokine deep sequencing disorder control economic cost effective therapy experimental study genome-wide immunoregulation improved in vivo inhibitor innovation insight interest kinase inhibitor mesenchymal stromal cell mouse model new therapeutic target novel peer prevent primary outcome programmed cell death ligand 1 response single-cell RNA sequencing systemic autoimmune disease tertiary lymphoid organ therapeutic development tissue repair treatment group

项目摘要

PROJECT SUMMARY Sjӧgren’s disease (SjD), a common systemic autoimmune disease characterized by marked oral and ocular sicca, has no disease modifying treatments available. Our long-term goal is to develop new effective therapies for SjD. The objective of this application is to determine the mechanism through which ruxolitinib inhibits IFN- induced pro-inflammatory salivary gland mesenchymal stromal cells (MSCs) and define the effects of ruxolitinib on disease activity in SjD mouse models. The central hypothesis of the proposed studies is that IFN- stimulated SG-MSCs, through STAT1 signaling, are pro-inflammatory and that ruxolitinib inhibits this pro- inflammatory phenotype and ultimately reduces SG inflammation and restores saliva production in SjD mouse models. The rationale for this hypothesis is based on our new data showing ruxolitinib abolishes IFN-induced MSC activation and reduces MHCII upregulation in vitro through STAT1. These new data are pivotal because they identify a possible mechanism by which the pro-inflammatory aspect of MSCs can be modified. The central hypothesis will be tested by pursuing two specific aims: (1) Determine the effect of ruxolitinib on SG- MSC immunobiology in vitro and (2) define the effects of ruxolitinib on SG-MSC and whole gland phenotype and function in vivo. Under the first aim, SG-MSCs from SjD and control patients will be treated with IFN ± ruxolitinib and phenotype and functional differences will be examined in vitro. Chromatin immunoprecipitation- sequencing will be performed to determine the mechanism by which ruxolitinib imparts change in the immunomodulatory profile of SG-MSCs. For the second aim, two SjD mouse models will be treated with ruxolitinib or vehicle. SG-MSCs will be isolated and interrogated from each treatment group. Next, a global salivary gland and systemic evaluation will be performed. The research proposed in this application is innovative because traditionally the anti-inflammatory profile of IFN-treated MSCs has been the focus of research. This proposal focuses on how IFN creates a pro-inflammatory MSC phenotype that can be inhibited with ruxolitinib. Furthermore, SjD research has focused on JAK1 inhibition and we propose the use of a JAK1 & 2 inhibitor to treat SjD. The proposed research is significant because ruxolitinib holds promise as a feasible modality to promote anti-inflammatory resident MSCs and for systemic SjD treatment. Should this pilot study determine the mechanism by which ruxolitinib creates anti-inflammatory MSCs or that ruxolitinib improves SjD in mice, these finding will be harnessed toward novel MSC-based or systemic treatment of SjD.

项目概要干燥病（SjD）是一种常见的全身性自身免疫性疾病，其特征是明显的口腔和眼部病变干燥症，没有可用的疾病缓解治疗方法，我们的长期目标是开发新的有效疗法。本申请的目的是确定鲁索替尼抑制 IFN-的机制。诱导促炎唾液腺间充质基质细胞 (MSC) 并确定鲁索替尼的作用所提出的研究的中心假设是 IFN-α。通过 STAT1 信号传导刺激的 SG-MSC 具有促炎作用，而鲁索替尼可抑制这种促炎作用。炎症表型，最终减少 SjD 小鼠的 SG 炎症并恢复唾液产生这一假设的基本原理是基于我们的新数据，显示鲁索替尼消除了 IFN-诱导的。 MSC 激活并通过 STAT1 减少体外 MHCII 上调这些新数据至关重要，因为他们确定了一种可能的机制，通过该机制可以改变间充质干细胞的促炎作用。将通过追求两个具体目标来检验中心假设：（1）确定鲁索替尼对 SG- MSC 体外免疫生物学和 (2) 定义鲁索替尼对 SG-MSC 和全腺体表型的影响在第一个目标下，来自 SjD 和对照患者的 SG-MSC 将接受 IFN-± 治疗。鲁索替尼以及表型和功能差异将在体外进行染色质免疫沉淀检查。将进行测序以确定鲁索替尼引起改变的机制 SG-MSC 的免疫调节特性对于第二个目标，将使用两种 SjD 小鼠模型进行治疗。接下来，将从每个治疗组中分离并检查 ruxolitinib 或载体。将进行唾液腺和系统评估。创新是因为传统上 IFN- 处理的 MSC 的抗炎特性一直是研究的焦点该提案的重点是 IFNα 如何产生可被抑制的促炎 MSC 表型。此外，SjD 研究重点是 JAK1 抑制，我们建议使用 JAK1。 &2 抑制剂治疗 SjD 的研究意义重大，因为鲁索替尼有望成为一种可行的药物。促进抗炎驻留间充质干细胞和系统性 SjD 治疗的方式是否应该进行这项试点研究。确定鲁索替尼产生抗炎 MSC 或鲁索替尼改善 SjD 的机制在小鼠中，这些发现将被用于基于 MSC 的新型或系统性 SjD 治疗。