Adenosine Receptors and Restoration of Salivary Gland in Sjogren's Syndrome

腺苷受体与干燥综合征唾液腺的恢复

• 批准号: 8390609
• 负责人: Umesh S Deshmukh
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8390609
• 关键词: ADORA3 gene; Acinus organ component; Address; Adenosine; Adjuvant; Affect; Agonist; Amylases; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Cardiovascular system; Cell Line; Cells; Characteristics; Chronic; Clinical Treatment; Clinical Trials; Coupled; Cyclic AMP; Data; Disease; Drug Delivery Systems; Drug vehicle; Dry Eye Syndromes; Electron Microscopy; Exocrine Glands; Female; Functional disorder; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Goals; Histocytochemistry; Human; Immune; Immunosuppression; Inflammatory; Injury; Ion Channel Protein; Link; MAPK3 gene; Measures; Mission; Modeling; Monitor; Mus; National Institute of Dental and Craniofacial Research; Neurologic; Oral health; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phosphorylation; Pilocarpine; Play; Production; Purinergic P1 Receptors; Recovery; Regimen; Reporting; Respiratory System; Role; Saliva; Salivary; Salivary Glands; Serum; Severities; Sialadenitis; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Structure; Submandibular gland; Symptoms; Syndrome; Testing; Therapeutic; Time; Tissues; Xerostomia; angiogenesis; cytokine; drug candidate; in vivo; loss of function; mouse model; receptor; receptor expression; research study; response; restoration; saliva secretion; tissue repair

DESCRIPTION (provided by applicant): Dry mouth is one of the major complications of Sj¿gren's Syndrome (SS), a chronic autoimmune disorder mainly affecting the exocrine glands. The current therapies for treating dry mouth in SS are predominantly directed towards providing symptomatic relief. Clearly, therapeutic regimens capable of suppressing an ongoing autoimmune response coupled with restoration of salivary gland function will be critical for providing long term relief. The major goal of this application is to evaluate adenosine receptor (AR) agonists as candidate drugs for restoring salivary gland function in a spontaneous mouse model for SS. Adenosine, a major anti-inflammatory metabolite, signals through four G protein coupled receptors termed A1AR, A2aAR, A2bAR and A3AR. This application will test the hypothesis that AR agonists, particularly those targeting the A2aAR and A2bAR, will restore salivary gland function in SS by suppressing an ongoing autoimmune response as well as by directly affecting the salivary gland function. The hypothesis will be investigated in a spontaneous mouse model for SS. Female mice with fully developed symptoms of SS will be treated with AR agonists and restoration of salivary gland function monitored by measuring pilocarpine induced salivation. Systemic immunosuppressive effects of AR agonists will be monitored by measuring autoantibody responses and serum cytokine levels. Localized immunosuppression within the salivary glands will be studied by analyzing gene expression levels of different pro-inflammatory cytokines within the submandibular glands and degree of sialoadenitis. To determine direct effects of AR agonists on salivary glands, Ca2+ mobilization and phosphorylation of ERK1/2 in submandibular gland acini will be monitored. Several adenosine receptor agonists have either completed or are currently undergoing human clinical trials for different indications. The successful completion of this application will provide a majo impetus for advancing these drugs to human clinical trials for restoration of salivary gland function in SS. This application is closely aligned and highly significant for the missions of NIDCR and the improvement of oral health. PUBLIC HEALTH RELEVANCE: This application will test the ability of drugs targeting a certain class of receptors called the adenosine receptors for restoring salivary gland function in a mouse model for Sj¿gren's syndrome. Successful completion of this application will pave the way for future human clinical trials for treating dry mouth.

描述(申请人提供)：口干是干燥综合征(SS)的主要并发症之一，SS是一种主要影响外分泌腺的慢性自身免疫性疾病。目前治疗SS口干的治疗方法主要是针对症状缓解。显然，能够抑制正在进行的自身免疫反应并恢复唾液腺功能的治疗方案将是提供长期缓解的关键。该应用的主要目的是评价腺苷受体(AR)激动剂作为恢复唾液腺功能的候选药物在自发性SS小鼠模型中的作用。腺苷是一种主要的抗炎代谢产物，通过四种G蛋白偶联受体A1AR、A2aAR、A2bAR和A3AR传递信号。这项应用将检验AR激动剂，特别是那些针对A2aAR和A2bAR的激动剂，将通过抑制正在进行的自身免疫反应以及直接影响唾液腺功能来恢复SS的唾液腺功能的假设。这一假说将在SS的自发小鼠模型中进行研究。SS症状完全发展的雌性小鼠将接受AR激动剂治疗，并通过测量匹罗卡品诱导的唾液来监测唾液腺功能的恢复。AR激动剂的全身性免疫抑制效应将通过测量自身抗体反应和血清细胞因子水平来监测。将通过分析颌下腺内不同促炎细胞因子的基因表达水平和涎腺炎的程度来研究唾液腺内的局部免疫抑制。为了确定AR激动剂对唾液腺的直接影响，将监测颌下腺腺泡内钙离子的动员和ERK1/2的磷酸化。几种腺苷受体激动剂已经完成或正在进行不同适应症的人体临床试验。该申请的成功完成将为将这些药物推向恢复SS唾液腺功能的人体临床试验提供强大的动力。这一应用对NIDCR的使命和改善口腔健康具有密切的一致性和非常重要的意义。 公共卫生相关性：这项应用将测试针对特定类型的受体的药物恢复干燥综合征小鼠唾液腺功能的能力。这项应用的成功完成将为未来治疗口干的人类临床试验铺平道路。