Resolution of Cytokine-Mediated Salivary Gland Inflammation

描述（由申请人提供）：干燥综合征（SS）是一种自身免疫性疾病，影响1%的人口。SS的特征是口干和眼干。这些症状通常只有在唾液腺和泪腺显示慢性炎症后才能在临床上检测到，而目前的治疗方法对此没有任何益处。虽然已经进行了广泛的调查，以了解ethiopathogenesis的SS，原因或治疗的疾病仍然是未知的。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）转化为消退素（Rv），消退素是一种新型的、高效的抗炎剂，其控制结肠炎、牙周炎和角膜炎症模型中的炎症消退。此外，我们最近的研究结果表明，RvD 1受体ALX在正常唾液细胞中表达，以及在唾液来源的细胞系。在唾液腺上皮中，RvD 1阻断TNFα介导的腺泡形成的破坏，并通过PI 3 k/Akt途径增强上皮完整性。此外，在疾病发作之前（在4周龄时）用AT-RvD 1治疗SS小鼠模型可预防在疾病发作期间（在16周龄时）发生的下颌下腺中的分泌功能障碍和淋巴细胞浸润。因此，拟议的研究将阐明RvD 1和AT-RvD 1预防炎症功能障碍和恢复唾液上皮完整性的机制，使用公认的SS的体外和体内唾液模型。我们假设，唾液腺炎症的解决可以预防，并可能有助于管理，SS的症状。我们计划解决以下问题：目的1：描述唾液腺中RvD 1产生的途径。我们将研究参与RvD 1生物合成的酶和代谢产物是否在SS进展过程中发生改变。目的2：研究RvD 1在唾液腺中的下游信号通路。我们将研究RvD 1与ALXR结合并激活细胞迁移、细胞极性和细胞存活（在原代小鼠SMG细胞和唾液细胞系中）的机制。目的3：评价RvD 1治疗的功效（即，预防炎症和分泌功能障碍的能力）。我们相信，更好地了解RvD 1的生物发生、信号传导和治疗可以减少早期患者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.