Targeting P2 Receptors to Restore Salivary and Lacrimal Gland Function in Sjogren's Syndrome

靶向 P2 受体以恢复干燥综合征患者的唾液腺和泪腺功能

基本信息

批准号：
10685136
负责人：
GARY Andrew WEISMAN
金额：
$ 5.97万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685136
关键词：
Acinar Cell Affect Agonist American Apoptosis Archives Artificial Saliva Artificial Tears Autoantibodies Autoimmune Diseases Autoimmunity Autologous Bacterial Infections Biopsy CD28 gene Cadaver Cell Surface Receptors Cell surface Cells Chemicals Chronic Clinical Trials Coupled Crohn&apos s disease Dental caries Deterioration Development Digestive System Disorders Disease Drainage procedure Drops Dry Eye Syndromes Epithelial Epithelial Cells Exhibits Female Fibrosis Film Fluids and Secretions Functional disorder GTP-Binding Proteins Goals Human Hydration status Immune Immune response Immunomodulators In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Interferon Type II Interleukin-1 beta Interleukin-18 Interleukins Ion Channel Gating Knock-out Lacrimal gland structure Lead Lupus Lymphocyte Lymphoma Mediating Minor Minor salivary gland structure Mus Muscarinic Acetylcholine Receptor Nucleotides Ocular Pathology Oral Pathology P2Y2 receptor Pathogenesis Patients Periodontitis Phase Play Process Production Productivity Quality of life Receptor Activation Receptor Signaling Research Residual state Rheumatoid Arthritis Role Saliva Salivary Gland Diseases Salivary Glands Secondary to Serum Sialadenitis Signal Pathway Site Sjogren&apos s Syndrome Submandibular gland Systemic Lupus Erythematosus Testing Throat Cancer Tissues Transgenic Organisms Vision Woman Work Xerophthalmia Xerostomia antagonist autoimmune exocrinopathy cancer surgery cell injury cell motility cytokine extracellular eye dryness in vivo inflammatory marker injured innovation mouse model novel ocular pain ocular surface preservation prevent receptor receptor expression receptor upregulation response saliva secretion spatiotemporal symptom management tissue degeneration yeast infection

项目摘要

Summary Sjögren’s syndrome (SS), an autoimmune exocrinopathy of the salivary and lacrimal glands, affects ~ 4 million Americans, 90% of whom are women. SS is characterized by sialadenitis and dacryoadenitis, decreased saliva (i.e., xerostomia) and tear production (i.e., xerophthalmia) and the presence in blood serum of autoantibodies against Ro/SSA and La/SSB. Xerostomia and xerophthalmia in SS patients can lead to periodontitis, yeast and bacterial infections, digestive disorders and vision deterioration that severely reduce the quality of life for patients. Ultimately, chronic inflammation in SS leads to secondary autoimmune diseases, tissue fibrosis and lymphoma. Therapy for SS is limited to symptom management through external hydration, artificial saliva and tears and muscarinic receptor agonists that induce fluid secretion from residual exocrine acinar cells. Such remedies are universally judged to be inadequate and thus, development of more effective SS treatments is essential. Our research focuses on cell surface P2X7 and P2Y2 receptors for extracellular ATP, the intracellular chemical form of energy that when released from damaged salivary glands initiate inflammatory responses. Our studies show that P2X7R and P2Y2R antagonists enhance saliva secretion and reduce lymphocytic foci in salivary glands of two different mouse models of SS. Antagonism of the P2X7R also reduces lymphocytic accumulation in the lacrimal glands and increases tear secretion. These antagonists have not been used to treat human SS, although P2X7R is upregulated in salivary glands of SS patients compared to non-SS controls. P2X7R activation in salivary glands also induces maturation and release of IL-1β, an SS- related cytokine that upregulates P2Y2R in immune and epithelial cells, suggesting that P2X7R and P2Y2R contribute together to SS development. This project will investigate the ability of P2X7R and/or P2Y2R antagonists to increase saliva and/or tear secretion and reduce sialadenitis and/or dacryoadenitis in mouse models of SS. These findings will be validated by assessing P2X7R and P2Y2R expression in archived human SS and control minor salivary gland biopsies and evaluating effects of P2X7R and/or P2Y2R antagonism in freshly isolated human salivary and lacrimal gland cells. Specific Aim 1 will investigate the hypothesis that P2X7R and P2Y2R play sequential roles in chronic sialadenitis and glandular dysfunction in SS mouse models and can be antagonized to treat SS in vivo. Specific Aim 2 will investigate the hypothesis that P2X7R and P2Y2R activation in lacrimal gland epithelial cells promotes dry eye disease in mouse models of SS. Specific Aim 3 will investigate P2X7R and P2Y2R-mediated proinflammatory responses in human primary salivary and lacrimal gland cells and human SS minor salivary gland biopsies. Successful completion of this proposal will represent a critical step towards realization of the ultimate goal of targeting the P2X7R and/or P2Y2R to treat SS in humans.

概括干燥综合征 (SS) 是一种唾液腺和泪腺的自身免疫性外泌体病，影响 ~ 4 百万美国人，其中 90% 是女性，患有唾液腺炎和泪腺炎，唾液（即口干症）和泪液产生（即干眼症）以及血清中的存在 SS 患者的 Ro/SSA 和 La/SSB 自身抗体的增加可导致口干症和干眼症。牙周炎、酵母菌和细菌感染、消化系统疾病和视力下降，严重降低最终，SS 的慢性炎症会导致继发性自身免疫性疾病，组织纤维化和淋巴瘤的治疗仅限于通过外部补水来控制症状，人工唾液和眼泪以及毒蕈碱受体激动剂，诱导残余外分泌液分泌人们普遍认为这种疗法是不够的，因此需要开发更有效的疗法。 SS 治疗至关重要。我们的研究重点是细胞表面 P2X7 和 P2Y2 细胞外受体。 ATP，细胞内化学形式的能量，当从受损的唾液腺释放时会启动我们的研究表明 P2X7R 和 P2Y2R 拮抗剂可增强唾液分泌和减少两种不同 SS 小鼠模型唾液腺中的淋巴细胞灶。P2X7R 的拮抗作用。这些拮抗剂可以减少泪腺中的淋巴细胞积聚并增加泪液分泌。尚未用于治疗人类 SS，尽管与相比，P2X7R 在 SS 患者的唾液腺中表达上调对于非 SS 对照，唾液腺中的 P2X7R 激活也会诱导 IL-1β（一种 SS-）的成熟和释放。上调免疫细胞和上皮细胞中 P2Y2R 的相关细胞因子，表明 P2X7R 和 P2Y2R 共同为 SS 的开发做出贡献。该项目将研究 P2X7R 和/或 P2Y2R 的能力。增加小鼠唾液和/或泪液分泌并减少唾液腺炎和/或泪腺炎的拮抗剂这些发现将通过评估存档的人类中 P2X7R 和 P2Y2R 的表达来验证。 SS 和对照小唾液腺活检并评估 P2X7R 和/或 P2Y2R 拮抗作用在新鲜分离的人类唾液和泪腺细胞将研究以下假设： P2X7R 和 P2Y2R 在 SS 小鼠模型的慢性唾液腺炎和腺体功能障碍中发挥连续作用并且可以在体内拮抗治疗SS。具体目标2将研究P2X7R和P2X7R的假设。泪腺上皮细胞中的 P2Y2R 激活促进 SS 特异性小鼠模型的干眼病。目标 3 将研究人类原发唾液中 P2X7R 和 P2Y2R 介导的促炎症反应泪腺细胞和人类 SS 小唾液腺活组织检查将成功完成此提案。代表着实现靶向 P2X7R 和/或 P2Y2R 治疗的最终目标的关键一步人类中的SS。