The role of the P2X7 receptor in radiation-induced salivary gland inflammation and dysfunction

P2X7受体在辐射引起的唾液腺炎症和功能障碍中的作用

• 批准号: 9755804
• 负责人: Kristy Ellen Gilman Creitz
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-14 至 2021-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755804
• 关键词: Acute; Antioxidants; Apoptosis; Apoptotic; Cells; Chronic; Complement; Dinoprostone; Disease; Eicosanoids; Epithelial Cells; Evaluation; Functional disorder; Goals; Head and Neck Cancer; Head and neck structure; Histologic; Hour; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Intestines; Ionizing radiation; Knock-out; Lead; Lung; Maintenance; Mammary gland; Mediating; Molecular; Mus; Normal tissue morphology; Operative Surgical Procedures; Outcome; Palliative Care; Pathway interactions; Patients; Phagocytes; Phagocytosis; Population; Prevention; Process; Production; Purinoceptor; Quality of life; Radiation; Radiation exposure; Radiation induced damage; Radiation therapy; Reactive Oxygen Species; Receptor Activation; Receptor Inhibition; Research; Research Project Grants; Role; Salivary; Salivary Glands; Signal Pathway; Signal Transduction; Testing; Time; Tissue Preservation; Tissues; Wild Type Mouse; Work; Xerostomia; cancer diagnosis; cancer therapy; cell injury; cell type; clinical translation; cytokine; experimental study; extracellular; head and neck cancer patient; improved; in vivo; irradiation; knock-down; loss of function; macrophage; new therapeutic target; novel; preservation; prevent; radiation response; receptor; receptor binding; recruit; repaired; response; side effect; tissue repair; tumor

Project Abstract: Over 60,000 cases of head and neck cancer are diagnosed in the US annually with typical treatment including surgery and radiation. Radiation therapy causes collateral damage to nearby normal tissues, particularly the salivary glands, which results in chronic hyposalivation and xerostomia. Currently only limited palliative treatment options exist, therefore the mechanisms behind radiation-induced salivary gland dysfunction should be investigated further. It is well-established that radiation causes production of reactive oxygen species (ROS), which leads to secretion of pro-inflammatory signals (i.e. cytokines, eicosanoids) to recruit immune cells to aid in tissue repair. The P2X7 receptor (P2X7R) is highly expressed on salivary epithelial cells, mediates ROS, interleukin-1 and prostaglandin E2 production and is activated following radiation. P2X7R is a purinergic receptor activated by high levels of extracellular ATP (>100M) that are often secreted during inflammation. While a select number of cytokines and eicosanoids have been investigated following radiation, the network of inflammatory signals and phagocytic cell activity has not been fully elucidated, nor has the role of the P2X7R in these pathways. The goal of this proposal is to evaluate the integrated network of inflammatory signals, the downstream signaling cascades induced, the predominant phagocytic cell type and the role of the P2X7R in these processes in the salivary gland following radiation exposure. We hypothesize that radiation-induced salivary gland dysfunction occurs due to P2X7R-mediated pro-inflammatory signaling, and tissue-resident macrophages are the predominant phagocytic cell type in salivary tissue. To test this hypothesis, we will unbiasedly quantify the full network of inflammatory signals (i.e., cytokines and eicosanoids) produced by salivary epithelial cells following radiation exposure and determine downstream pathways induced by these signals through evaluation of receptor binding and activation of intracellular signaling cascades. Further, we will evaluate the predominant phagocytic cell population, the inflammatory signals generated following engulfment of radiation-induced apoptotic cells and determine the activity of tissue-resident macrophages post-radiation. The role of the P2X7R will be determined by comparing the results of the proposed experiments of wild type mice to that of P2X7R knockout (P2X7R-/-) or P2X7R antagonist (A438079)-treated mice. Previous work has shown that P2X7R knockdown allows for sustained salivary function following radiation in mice and inhibition with the P2X7R antagonist may prove to be a novel therapeutic target for normal tissue preservation during radiation therapy. The long-term outcomes of this project will provide an unbiased understanding of the acute and chronic inflammatory response occurring in salivary epithelial cells following radiation damage and uncover the role of the P2X7 receptor in radiation-induced inflammation. This may impact fields beyond salivary gland research, as these results should be expandable to other types of tissues and forms of tissue damage.

项目摘要：在美国，每年有超过6万例头颈癌被诊断为典型的 治疗包括手术和放射治疗。放射治疗会对附近的正常组织造成附带损害， 尤其是唾液腺，会导致慢性淋巴功能减退和口干。目前仅限于 姑息治疗的选择是存在的，因此辐射导致唾液腺功能障碍的机制 应该进一步调查。众所周知，辐射会导致活性氧的产生。 (ROS)，导致分泌促炎信号(即细胞因子、二十烷类化合物)以招募免疫细胞 以帮助组织修复。P2X7受体(P2X7R)在唾液上皮细胞上高度表达，介导ROS， 白介素1和前列腺素E2产生，并在辐射后被激活。P2X7R是一种嘌呤能 高水平的胞外三磷酸腺苷(&gt；100M)激活的受体，通常在炎症过程中分泌。 虽然在辐射后对一些细胞因子和二十烷类化合物进行了研究，但 炎症信号和吞噬细胞活性尚未完全阐明，也没有P2X7R在 这些小路。这项建议的目标是评估炎症信号的综合网络， 诱导的下游信号级联反应、主要吞噬细胞类型和P2X7R在血管内皮细胞中的作用 辐射暴露后唾液腺中的这些过程。我们假设辐射引起的 唾液腺功能障碍是由于P2X7R介导的促炎信号，以及组织驻留 巨噬细胞是唾液组织中的主要吞噬细胞类型。为了检验这一假设，我们将 公正地量化唾液产生的炎症信号(即细胞因子和二十烷类化合物)的完整网络 辐射后的上皮细胞并确定由这些信号诱导的下游通路 通过评估受体结合和激活细胞内信号级联反应。此外，我们将评估 主要的吞噬细胞群，吞噬后产生的炎症信号 辐射诱导细胞凋亡，并测定辐射后组织驻留巨噬细胞的活性。这个 P2X7R的作用将通过比较野生型小鼠和野生型小鼠的实验结果来确定 P2X7R基因敲除(P2X7R-/-)或P2X7R拮抗剂(A438079)处理的小鼠。先前的研究表明， P2X7R基因敲除使小鼠在接受辐射和抑制P2X7R后持续的唾液功能 拮抗剂可能成为放射治疗期间保存正常组织的一种新的治疗靶点。 该项目的长期成果将提供对急性和慢性疾病的公正理解 唾液上皮细胞辐射损伤后的炎症反应及其作用机制 P2X7受体在放射性炎症中的作用这可能会影响唾液腺研究以外的领域，如 这些结果应该可以扩展到其他类型的组织和形式的组织损伤。