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数百万美国人，他们的生活质量受到口干、口腔细菌感染、营养不良和其他与唾液产生减少相关的疾病的严重影响。唾液分泌减少在干燥综合征（SS）中最常见，这是一种病因不明的自身免疫性外分泌病，唾液分泌减少，随后出现唾液腺淋巴细胞浸润，最终导致组织变性。此外，唾液腺炎症和唾液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潜在机制将有助于确定目前无法获得的治疗选择来治疗唾液腺变性。现在已经充分认识到，高水平的细胞内核苷酸，特别是 在病理条件下，细胞响应炎症、应激或创伤而释放ATP。我们的研究集中在了解参与唾液腺炎症和变性的ATP依赖性机制。我们小组最近的工作表明，唾液腺炎症可以通过激活P2 X7受体（P2 X7 R）来引发，P2 X7受体是一种ATP门控的非选择性阳离子通道，其也促进几种慢性疾病中的炎症和细胞凋亡，包括类风湿性关节炎、肺纤维化以及神经退行性和炎性肠病。本提案中提出的初步研究表明，与对照小鼠相比，当用BzATP（我们最初开发的一种高亲和力P2 X7 R配体）灌注腺体时，P2 X7 R-/-小鼠的中性粒细胞募集到导管结扎的下颌下腺（SMG）显著减少。因此，我们将利用原代分离的唾液腺细胞和野生型和P2 X7 R-/-小鼠中唾液腺炎症的导管结扎模型来阐明与P2 X7 R相关的炎症反应是否在功能性SMG变性中起重要作用以及所涉及的机制（具体目标1）。其他的研究将把这些结果扩展到辐射诱导的唾液腺损伤的小鼠模型（特异性目标2）和自身免疫性外分泌病（具体目标3），其中P2 X7 R-/-小鼠和P2 X7 R-选择性拮抗剂的可用性（目前正在进行治疗类风湿性关节炎和脊髓损伤的临床试验）将使我们能够直接检查体内P2 X7 R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P2 X7 R活性的抑制是否可以保护唾液腺免受小鼠中各种形式的组织损伤，这最终将是开发人类唾液功能障碍的治疗所必需的。