Resolution of Cytokine-Mediated Salivary Gland Inflammation

描述(由申请人提供)：干燥综合征(SS)是一种影响1%人口的自身免疫性疾病。SS的特征是口干、眼干。这种症状通常只有在唾液和泪腺出现慢性炎症后才能在临床上发现，目前的治疗方法在这一点上没有任何益处。虽然对SS的民族致病机制进行了广泛的研究，但其病因或治疗方法仍不清楚。最近的研究表明，人类和动物细胞将ω-3多不饱和脂肪酸(PUFA)转化为溶血素(RV)，RV是一种新的、高效的抗炎药，可以控制结肠炎、牙周炎和角膜炎症模型中的炎症消退。此外，我们最近的发现表明，RvD1受体ALX在正常唾液细胞中表达，也在唾液来源的细胞系中表达。在唾液上皮，Rvd1通过PI3K/Akt通路阻断肿瘤坏死因子α介导的腺泡形成的破坏，并增强上皮的完整性。此外，在发病前(4周龄)用AT-RvD1治疗SS小鼠模型可预防发病期间(16周龄)发生的颌下腺分泌功能障碍和淋巴细胞渗透。因此，本研究将利用公认的唾液SS体外和体内模型，阐明RvD1和AT-RvD1预防炎症功能障碍和恢复唾液上皮完整性的机制。我们假设，唾液腺炎症的消退可以预防和帮助管理SS的症状。我们计划解决以下问题：目标1：研究唾液腺中RvD1的生成途径。我们将研究参与RvD1生物合成的酶和代谢物是否在SS的进展过程中发生变化。目的：研究RvD1在唾液腺中触发的下游信号通路。我们将研究RvD1与ALXR结合并激活细胞迁移、细胞极性和细胞存活的机制(在原代小鼠SMG细胞和唾液细胞系中)。目的：评价RvD1对SS小鼠模型的治疗效果(即预防炎症和分泌功能障碍的能力)。我们相信，更好地了解RvD1的生物发生、信号传递和治疗可以减缓早期患者SS的进展，并改善晚期患者的症状管理。

DESCRIPTION (provided by applicant): Sjögren's Syndrome (SS) is an autoimmune disease affecting 1% of the population. The hallmarks of SS are dry mouth and dry eyes. Such symptoms are typically clinically detectable only after salivary and lacrimal glands display chronic inflammation, a point at which current therapies have no benefit. Although extensive investigation has been done to understand the ethiopathogenesis of SS, the causes or cures for the disease are still unknown. Recent studies demonstrate that human and animal cells convert ω-3 polyunsaturated fatty acids (PUFAs) into resolvins (Rv), which are new, highly potent, anti-inflammatory agents that control the resolution of inflammation in models colitis, periodontitis and corneal inflammation. Additionally, our recent findings indicate that the RvD1 receptor ALX is expressed in normal salivary cells, as well in cell lines of salivary origin. In salivary epitheium, RvD1 blocks TNFα-mediated disruption of acinar formation and enhances epithelial integrity via PI3k/Akt pathways. Furthermore, treatment of a SS mouse model with AT-RvD1 before disease onset (at 4 weeks of age) prevents secretory dysfunction and lymphocytic infiltration in submandibular glands that occurs during onset of the disease (at 16-weeks of age). Therefore, the proposed studies will elucidate the mechanisms whereby RvD1 and AT-RvD1 prevent inflammatory dysfunction and restore salivary epithelial integrity, using accepted in vitro and in vivo salivary models of SS. We hypothesize that resolution of inflammation in salivary glands can prevent, and could help manage, symptoms of SS. We plan to address the following: Aim 1: To characterize the pathways involved in the generation of RvD1 in salivary glands. We will investigate whether enzymes and metabolites involved in the biosynthesis of RvD1 are altered during the progression of SS. Aim 2: To investigate the downstream signaling pathways triggered by RvD1 in salivary glands. We will study the mechanisms by which RvD1 binds to the ALXR and activates cell migration, cell polarity, and cell survival (in primary mouse SMG cells and in salivary cell lines). Aim 3: To evaluate the efficacy of the RvD1 treatment (i.e., the abiliy to prevent inflammation and secretory dysfunction) in SS mice models. We believe a better understanding of RvD1 biogenesis, signaling, and treatment could reduce the progress of SS in earlier stage patients and lead to improved symptom management for advanced stage patients.