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，干燥综合征是一种主要影响外分泌腺的慢性自身免疫性疾病。目前用于治疗SS口干的疗法主要针对提供症状缓解。显然，治疗方案能够抑制正在进行的自身免疫反应加上唾液腺功能的恢复将是至关重要的，以提供长期的缓解。本申请的主要目的是评估腺苷受体（AR）激动剂作为候选药物，用于恢复自发性SS小鼠模型中的唾液腺功能。腺苷是一种主要的抗炎代谢物，通过四种G蛋白偶联受体A1 AR、A2 aAR、A2 bAR和A3 AR发出信号。本申请将检验以下假设：AR激动剂，特别是靶向A2 aAR和A2 bAR的AR激动剂，将通过抑制正在进行的自身免疫应答以及通过直接影响唾液腺功能来恢复SS中的唾液腺功能。将在自发性SS小鼠模型中研究该假设。将用AR激动剂治疗具有完全发展的SS症状的雌性小鼠，并通过测量毛果芸香碱诱导的流涎来监测唾液腺功能的恢复。将通过测量自身抗体应答和血清细胞因子水平监测AR激动剂的全身免疫抑制作用。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作用，将监测下颌下腺腺泡中的Ca 2+动员和ERK 1/2的磷酸化。几种腺苷受体激动剂已经完成或目前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用于恢复SS中唾液腺功能的人体临床试验提供主要动力。该应用程序与NIDCR的使命和改善口腔健康密切相关，具有重要意义。 公共卫生相关性：这项应用将测试靶向某种称为腺苷受体的受体的药物在干燥综合征小鼠模型中恢复唾液腺功能的能力。这项申请的成功完成将为未来治疗口干的人体临床试验铺平道路。

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.