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

描述（由申请人提供）：口干是干燥综合征（SS）的主要并发症之一，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口干的方法主要是为了提供症状缓解。显然，能够抑制自身免疫反应并恢复唾液腺功能的治疗方案对于提供长期缓解至关重要。本申请的主要目的是评估腺苷受体（AR）激动剂作为恢复SS自发性小鼠模型涎腺功能的候选药物。腺苷是一种主要的抗炎代谢物，通过四种G蛋白偶联受体A1AR、A2aAR、A2bAR和A3AR发出信号。该应用将验证AR激动剂，特别是针对A2aAR和A2bAR的激动剂，通过抑制持续的自身免疫反应以及直接影响唾液腺功能来恢复SS患者唾液腺功能的假设。该假设将在自发性SS小鼠模型中进行研究。患有SS症状的雌性小鼠将接受AR激动剂治疗，并通过测量匹罗卡品诱导的唾液分泌来监测唾液腺功能的恢复。AR激动剂的全身免疫抑制作用将通过测量自身抗体反应和血清细胞因子水平来监测。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，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，将监测下颌骨腺腺腺中Ca2+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推进这些药物进入恢复SS患者唾液腺功能的人体临床试验提供巨大的推动力。该申请对于NIDCR的使命和改善口腔健康具有密切的联系和高度的意义。

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.