Resolution of Cytokine-Mediated Salivary Gland Inflammation

描述（由申请人提供）：Sjögren综合征（SS）是一种影响1%人口的自身免疫性疾病。党卫军的特点是口干眼干。这些症状通常只有在唾液腺和泪腺表现出慢性炎症后才能在临床上检测到，而目前的治疗方法对慢性炎症没有任何益处。虽然已经进行了广泛的调查，以了解SS在埃塞俄比亚的发病机制，但该疾病的原因或治疗方法仍然未知。最近的研究表明，人类和动物细胞将ω-3多不饱和脂肪酸（PUFAs）转化为溶解蛋白（Rv），这是一种新的，高效的抗炎药物，可控制结肠炎，牙周炎和角膜炎症模型的炎症消退。此外，我们最近的研究结果表明，RvD1受体ALX在正常唾液细胞中表达，以及在唾液来源的细胞系中表达。在唾液上皮中，RvD1阻断tnf α介导的腺泡形成破坏，并通过PI3k/Akt通路增强上皮完整性。此外，在发病前（4周龄）用at - rvd1治疗SS小鼠模型，可防止发病时（16周龄）发生的分泌功能障碍和下颌腺淋巴细胞浸润。因此，我们提出的研究将阐明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，使用公认的体外和体内SS唾液模型。我们假设唾液腺炎症的解决可以预防并帮助控制SS症状。我们计划解决以下问题：目的1：表征唾液腺中RvD1生成的途径。我们将研究参与RvD1生物合成的酶和代谢物是否在SS的发展过程中发生改变。目的2：研究RvD1在唾液腺中引发的下游信号通路。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3：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、信号传导和治疗可以减少早期SS患者的进展，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.