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：
8460463
负责人：
Olga Juliana Baker
金额：
$ 37.27万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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/8460463
关键词：
Acids Address Affect Age Anabolism 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 Syndrome 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): Sj¿gren'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 ?-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 TNF¿-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（应用程序提供）：SJ¿Gren综合征（SS）是一种自身免疫性疾病，影响了1％的人口。 SS的标志是干嘴和干燥的眼睛。这种症状通常只能在唾液和泪网格表现出慢性感染后才能在临床上检测到，这一点当前疗法没有益处。尽管已经进行了广泛的研究以了解SS的征原病，但该疾病的原因或治疗方法仍然未知。最近的研究表明，人类和动物细胞转化了-3多不饱和脂肪酸（PUFAS）为resolvins（RV），这些脂肪酸（RV）是新的，高潜力的抗炎药，可控制模型结肠炎，牙周炎和角膜感染中炎症的分辨率。此外，我们最近的发现表明，RVD1受体ALX在正常的唾液细胞以及唾液起源细胞系中表达。在唾液上皮中，RVD1阻止了TNF介导的腺泡形成的破坏，并通过PI3K/AKT途径增强了上皮完整性。此外，在疾病发作前（4周龄）在疾病发作前用AT-RVD1治疗SS小鼠模型可防止秘密功能障碍和淋巴细胞浸润在疾病发作期间发生（在16周龄时）的下颌腺体中。因此，拟议的研究将阐明RVD1和AT-RVD1防止炎症功能障碍并使用SS的体外和体内唾液模型来防止炎症功能障碍并恢复唾液上皮完整性。我们假设唾液网格中炎症的分辨率可以预防，并且可以帮助管理SS的症状。我们计划解决以下内容：目标1：表征唾液网格中RVD1产生的途径。我们将研究AIM 2期间参与RVD1生物合成的酶和代谢产物是否会改变：研究由RVD1在唾液网格中触发的下游信号传导途径。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SS小鼠模型中RVD1治疗的效率（即防止注射和秘书功能障碍）的效率。我们认为，对RVD1生物发生，信号传导和治疗有更好的了解可以减少早期患者的SS进展，并改善晚期患者的症状管理。