Resolution of Cytokine-Mediated Salivary Gland Inflammation

细胞因子介导的唾液腺炎症的解决

基本信息

批准号：
9098091
负责人：
Olga Juliana Baker
金额：
$ 9.39万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098091
关键词：
Acids Address Affect Age Anabolism Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Aspirin Autoimmune Diseases Binding Biogenesis C10 Cell Line Cell Polarity Cell Survival Cells Chronic Colitis Cornea Data Diabetes Mellitus Disease Dryness Eicosapentaenoic Acid Enzymes Epithelial Epithelium Functional disorder Generations Goals Healed Human In Vitro Infiltration Inflammation Inflammatory Interferons Interleukin-12 Interleukin-18 Interleukin-6 Interleukins Investigation Lacrimal gland structure Lead Lipids Lipoxins Longevity Lymphocyte Major salivary gland structure Mediating Metabolic Pathway Minor salivary gland structure Modeling Molecular Mus Onset of illness Oral cavity Oral health Outcome PIK3CG gene Parotid Gland Pathway interactions Patients Periodontitis Pilot Projects Plasma Polyunsaturated Fatty Acids Population Rattus Resolution Role Salivary Salivary Glands Sample Size Series Signal Pathway Signal Transduction Sjogren&apos s Syndrome Staging Submandibular gland Symptoms Tight Junctions Tissues Tumor Necrosis Factor-alpha Xerostomia analog cell motility cytokine eye dryness healing improved in vivo lipid mediator lipoxin A4 lipoxin B4 migration mouse model prevent receptor response saliva secretion salivary cell symptom management

项目摘要

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.

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，其特征是口干和眼干，此类症状通常只有在唾液腺和泪腺出现慢性炎症后才能在临床上检测到。尽管已经进行了广泛的研究来了解 SS 的发病机制，但最近的研究表明，该疾病的原因或治疗方法仍然未知。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)，这是一种新型高效抗炎剂，可控制结肠炎、牙周炎和角膜炎症模型中炎症的消退。最近的研究结果表明，RvD1 受体 ALX 在正常唾液细胞以及唾液来源的细胞系中表达，在唾液上皮中，RvD1 阻断 TNFα 介导的腺泡形成和破坏。通过 PI3k/Akt 通路增强上皮完整性此外，在疾病发作前（4 周龄）用 AT-RvD1 治疗 SS 小鼠模型可预防疾病发作期间（16 周龄）发生的下颌下腺分泌功能障碍和淋巴细胞浸润。 - 周龄）因此，拟议的研究将阐明 RvD1 和 AT-RvD1 预防炎症功能障碍和恢复唾液的机制。上皮完整性，使用公认的 SS 体外和体内唾液模型我们致力于解决唾液腺炎症可以预防并帮助控制 SS 症状我们计划解决以下问题：目标 1：表征途径。我们将研究参与 RvD1 生物合成的酶和代谢物是否在 SS 进展过程中发生改变。唾液腺中的 RvD1。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）目标 3：评估 RvD1 的功效。 SS 小鼠模型中的 RvD1 治疗（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 生物发生、信号传导和治疗可以减少疾病的进展。早期患者的 SS 可以改善晚期患者的症状管理。