Restoring Salivary Gland Function by Reducing Nucleotide-induced Inflammation

通过减少核苷酸诱导的炎症来恢复唾液腺功能

• 批准号: 9185314
• 负责人: GARY Andrew WEISMAN
• 金额: $ 58.25万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-17 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185314
• 关键词: Adverse effects; Affect; Affinity; Alpha Cell; American; Apoptosis; Apoptotic; Bacterial Infections; Biological Markers; Cations; Cell Death; Cell surface; Cells; Cellular Morphology; Chemicals; Chronic; Chronic Disease; Clinical Treatment; Clinical Trials; Disease; Duct (organ) structure; Epithelial Cells; Epithelium; Etiology; Event; Functional disorder; Gamma Rays; Gland; Goals; Head and Neck Cancer; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Ligands; Ligation; Lymphocyte; Modeling; Mus; Nerve Degeneration; Neutrophil Infiltration; Nucleotides; Oral; Pathologic; Play; Process; Production; Pulmonary Fibrosis; Quality of life; Radiation; Radiation induced damage; Receptor Activation; Receptor Signaling; Research; Rheumatoid Arthritis; Role; Saliva; Salivary; Salivary Gland Diseases; Salivary Gland Tissue; Salivary Glands; Signal Pathway; Sjogren' s Syndrome; Spinal cord injury; Stress; Submandibular gland; Therapeutic; Time; Tissues; Trauma; Wild Type Mouse; Work; Xerostomia; autoimmune exocrinopathy; base; extracellular; functional restoration; in vivo; in vivo Model; injured; loss of function; mouse model; nutrition; prevent; public health relevance; receptor; receptor function; response; saliva secretion; tissue degeneration; tumor growth

DESCRIPTION (provided by applicant): Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition, and other disorders that are associated with decreased saliva production. Loss of saliva production is most common in Sjögren's syndrome (SS), an autoimmune exocrinopathy of unknown etiology in which decreased saliva production is followed by lymphocytic infiltration of the salivary gland and ultimately tissue degeneration. In addition, salivary gland inflammation and hyposalivation is an unintended side effect of γ-radiation used for the treatment of head and neck cancers. Understanding the mechanisms underlying early events in salivary gland inflammation will help identify currently-unavailable therapeutic options to treat salivary gland degeneration. It is now well recognized that high levels of intracellular nucleotides, particularly ATP, are released from cells under pathological conditions in response to inflammation, stress or trauma. Our research has focused on understanding the ATP- dependent mechanisms involved in salivary gland inflammation and degeneration. Recent work by our group indicates that salivary gland inflammation can be initiated by activation of the P2X7 receptor (P2X7R), an ATP- gated, non-selective cation channel that also promotes inflammation and cell apoptosis in several chronic diseases, including rheumatoid arthritis, lung fibrosis, and neurodegenerative and inflammatory bowel diseases. Preliminary studies presented in this proposal indicate that neutrophil recruitment to duct-ligated submandibular gland (SMG) is significantly reduced in P2X7R-/- mice compared to control mice when the glands were perfused with BzATP, a high affinity P2X7R ligand that we initially developed. Therefore, we will utilize primary isolated salivary gland cells and the duct ligation model of salivary gland inflammation in wild type and P2X7R-/- mice to elucidate whether inflammatory responses associated with the P2X7R play a significant role in functional SMG degeneration and the mechanisms involved (Specific Aim 1). Other studies will extend these results to mouse models of radiation-induced salivary gland damage (Specific Aim 2) and autoimmune exocrinopathy (Specific Aim 3), where the availability of the P2X7R-/- mouse and P2X7R-selective antagonists (currently in clinical trials for the treatment of rheumatoid arthritis and spinal cord injury) will enable us to directly examine whether decreases in P2X7R function in vivo can retard salivary gland degeneration. Thus, the overall goal of these studies is to evaluate whether inhibition of P2X7R activity can protect the salivary gland from various forms of tissue damage in mice, which ultimately will be essential for developing treatments for human salivary dysfunction.

描述（由申请人提供）：唾液腺功能障碍影响着数百万美国人，他们的生活质量因口干、口腔细菌感染、营养不良和其他与唾液产生相关的疾病而严重下降。唾液分泌减少是最常见的。干燥综合征 (SS) 是一种病因不明的自身免疫性外泌体病，唾液分泌减少，随后出现唾液腺淋巴细胞浸润，最终导致唾液腺组织退化。炎症和唾液腺分泌不足是用于治疗头颈癌的 γ 辐射的意外副作用，了解唾液腺炎症早期事件的机制将有助于确定目前无法治疗唾液腺变性的治疗方案。认识到高水平的细胞内核苷酸，特别是 ATP 在病理条件下从细胞中释放，以应对炎症、压力或创伤。我们的研究重点是了解参与唾液腺炎症和退化的 ATP 依赖性机制。通过激活 P2X7 受体 (P2X7R)，P2X7 受体是一种 ATP 门控、非选择性阳离子通道，还可促进多种慢性疾病中的炎症和细胞凋亡，包括类风湿性关节炎、肺纤维化和神经退行性疾病该提案中提出的初步研究表明，当腺体灌注 BzATP（一种高亲和力 P2X7R 配体）时，与对照小鼠相比，P2X7R-/- 小鼠向导管结扎下颌下腺 (SMG) 的中性粒细胞募集显着减少。因此，我们将利用原代分离的唾液腺细胞和野生型和 P2X7R-/- 唾液腺炎症的导管结扎模型。小鼠以阐明与 P2X7R 相关的炎症反应是否在功能性 SMG 变性及其相关机制中发挥重要作用（具体目标 1），其他研究将这些结果扩展到辐射引起的唾液腺损伤的小鼠模型（具体目标 2）和自身免疫性外泌体病（具体目标 3），其中 P2X7R-/- 小鼠和 P2X7R-选择性拮抗剂（目前处于治疗临床试验中）的可用性类风湿性关节炎和脊髓损伤）将使我们能够直接检查体内 P2X7R 功能的降低是否可以延缓唾液腺变性。因此，这些研究的总体目标是评估 P2X7R 活性的抑制是否可以保护唾液腺免受各种影响。小鼠体内各种形式的组织损伤，这最终对于开发人类唾液功能障碍的治疗方法至关重要。