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

• 批准号: 10646349
• 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
• 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/10646349
• 关键词: Adipose tissue; Adult; Affect; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Autoantibodies; B-Lymphocytes; Biological; Bone Marrow; Cell Separation; 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; Infiltration; Inflammation; Inflammatory; Innovative Therapy; Interferon alpha; 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 Induction; Signal Transduction; Sjogren' 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; cell type; chromatin immunoprecipitation; cost; cytokine; deep sequencing; 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

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.

项目摘要 Sjnamegren病（SJD），一种常见的全身性自身免疫性疾病，特征在于口腔和眼部明显 Sicca，没有可用的疾病可用的疾病。我们的长期目标是开发新的有效疗法 对于SJD。该应用的目的是确定违反违反IFN-- 诱导促炎的唾液腺间充质基质细胞（MSC），并定义了鲁唑替尼的作用 SJD小鼠模型中的疾病活动。拟议的研究的中心假设是 通过STAT1信号传导刺激的SG-MSC是促炎性的，ruxolitinib抑制了这一点 炎症表型并最终减少SG注射并恢复SJD小鼠的唾液产生 型号。该假设的基本原理是基于我们的新数据，显示ruxolitinib废除了ifn诱导的 MSC激活并通过STAT1减少体外MHCII上调。这些新数据是关键的，因为 他们确定了可以修改MSC的促炎方面的可能机制。这 中央假设将通过追求两个具体目标来检验：（1）确定鲁唑替尼对SG-的影响 MSC在体外免疫生物学和（2）定义鲁唑替尼对SG-MSC和整个腺体表型的影响 并在体内功能。在第一个目标下，SJD和对照患者的SG-MSC将接受IFN±± 鲁唑替尼和表型以及功能差异将在体外检查。染色质免疫沉淀 将进行测序以确定ruxolitinib impparts在该机制中发生变化的机制 SG-MSC的免疫调节曲线。对于第二个目标，将处理两个SJD鼠标模型 鲁唑替尼或车辆。 SG-MSC将与每个治疗组分离和审问。接下来，一个全球 将进行唾液腺和全身评估。该应用程序提出的研究是 创新性是因为传统上，经过IFN处理的MSC的抗炎概况一直是 研究。该提案的重点是IFN如何创建可以抑制的促炎MSC表型 与鲁辛替尼。此外，SJD研究重点是JAK1抑制作用，我们建议使用JAK1 ＆2抑制剂治疗SJD。拟议的研究很重要 促进抗炎居民MSC和全身SJD治疗的模态。该试点研究应该 确定ruxolitinib创建抗炎MSC的机制或ruxolitinib改善SJD的机制 在小鼠中，这些发现将是针对新型MSC或SJD系统治疗的。