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（由申请人提供）：口干是干燥综合症（SS）的主要并发症之一，干燥综合症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 口干的疗法主要旨在缓解症状。显然，能够抑制持续的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。本申请的主要目标是评估腺苷受体 (AR) 激动剂作为在自发性 SS 小鼠模型中恢复唾液腺功能的候选药物。腺苷是一种主要的抗炎代谢物，通过称为 A1AR、A2aAR、A2bAR 和 A3AR 的四种 G 蛋白偶联受体发出信号。该应用将测试以下假设：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 中的唾液腺功能。该假设将在 SS 自发小鼠模型中进行研究。具有完全 SS 症状的雌性小鼠将接受 AR 激动剂治疗，并通过测量毛果芸香碱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唾液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，将监测下颌下腺腺泡中的 Ca2+ 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针对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进人体临床试验以恢复 SS 唾液腺功能提供重要动力。该应用程序与 NIDCR 的使命和改善口腔健康密切相关且非常重要。 公共健康相关性：本申请将测试针对某一类受体（称为腺苷受体）的药物在干燥综合征小鼠模型中恢复唾液腺功能的能力。该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。