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（由适用提供）：唾液腺功能障碍会影响数百万的美国人，其生活质量受到口干，口腔细菌感染，营养不良以及与改善唾液产生有关的其他疾病的严重影响。唾液产生的损失最为常见，在Sjögren综合征（SS）中，这是一种自身免疫性病因的自身免疫性外分病，其中改善的唾液产生后，随后是唾液腺的淋巴细胞浸润，最终是组织结肠化的。此外，唾液腺注射和脱落分解是用于治疗头颈癌的γ辐射的意外副作用。了解唾液腺注射早期事件的基础机制将有助于确定当前不可存放的治疗方法来治疗唾液腺变性。现在已经众所周知，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，响应炎症，压力或创伤。我们的研究集中在理解唾液腺感染和变性所涉及的ATP依赖机制。我们小组的最新工作表明，可以通过激活P2X7受体（P2X7R）激活唾液腺感染，P2X7受体（P2X7R）是一种ATP，非选择性的阳离子通道，在包括类风湿性关节炎，肺纤维化和神经脱发和炎症的几种慢性疾病中，还促进了几种慢性疾病的感染和细胞凋亡。该提案中介绍的初步研究表明，当P2X7R - / - 小鼠与对照小鼠相比，当我们最初开发的高亲和力P2X7R配体BZATP（一种高亲和力的P2X7R配体）灌注腺体时，P2X7R - / - 小鼠的神经磷脂募集到P2X7R - / - 小鼠中显着降低。因此，我们将利用野生型和p2x7r - / - 小鼠的唾液腺感染的主要孤立唾液腺细胞以及唾液腺感染的导管连接模型来阐明与P2X7R相关的炎症反应是否在功能SMG变性和所涉及的机制中起重要作用（特定的目标1）。其他研究将把这些结果扩展到辐射引起的唾液腺损伤（特定目标2）和自身免疫性外分病（特定目的3）的小鼠模型，其中P2X7R - / - 小鼠和P2X7R选择性拮抗剂的可用性（目前在临床试验中用于治疗脊髓炎和脊柱疾病的临床试验中）是否可以直接研究Rheeumatiot Cords ins in p2 sus inthrip tim per sipliby sy inthrithip sib tim pp cors inthritis炎和脊椎炎的疾病。可以阻碍唾液腺变性。这是这些研究的总体目标是评估抑制P2X7R活性是否可以保护唾液腺免受小鼠的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。