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：
10219752
负责人：
GARY Andrew WEISMAN
金额：
$ 61.16万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10219752
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 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 Sjögren's综合征（SS），一种唾液和泪腺的自身免疫性外分泌病，影响〜4 百万美国人，其中90％是女性。 SS的特征是sialadenitis和dacryoadenitis，减少唾液（即静脉静脉曲菌）和泪液产生（即血清病）以及血液序列的存在针对RO/SSA和LA/SSB的自动抗体。 SS患者中的心脏病和心脏病可能会导致牙周炎，酵母菌和细菌感染，消化系统疾病和视力恶化严重降低患者的生活质量。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。 SS的治疗仅限于通过外部水合的症状管理，人造唾液，眼泪和毒蕈碱受体激动剂，这些激动剂引起残留外分泌的流体分泌腺泡细胞。这种补救措施被普遍认为是不足的，因此，发展更有效 SS治疗至关重要。我们的研究重点是细胞外P2X7和P2Y2受体 ATP，细胞内化学形式的能量形式，从受损的唾液地面释放出来炎症反应。我们的研究表明，P2X7R和P2Y2R拮抗剂增强了唾液分泌和减少两个不同小鼠模型的唾液腺中的淋巴细胞灶。 P2X7R的对抗也减少泪腺上的淋巴细胞积累，并增加泪液分泌。这些对手有尽管在SS患者的唾液腺中更新了P2X7R，但并未用于治疗人类SS 到非SS控件。唾液腺中的P2X7R激活还诱导IL-1β的成熟和释放，SS- 与免疫细胞和上皮细胞中P2Y2R上调的相关细胞因子，表明P2X7R和P2Y2R 共同为SS开发做出贡献。该项目将研究P2X7R和/或P2Y2R的能力拮抗剂增加唾液和/或撕裂分泌，并减少小鼠中唾液酸炎和/或dacryoadenitis SS的模型。这些发现将通过评估存档人的P2X7R和P2Y2R表达来验证 SS和控制次要的唾液腺活检以及评估P2X7R和/或P2Y2R拮抗作用在新鲜分离的人类唾液和泪腺细胞。具体目标1将调查以下假设 P2X7R和P2Y2R在SS小鼠模型中在慢性唾液炎和腺功能障碍中起依次的作用并且可以拮抗以在体内治疗SS。具体目标2将研究p2x7r和泪腺上皮细胞中的P2Y2R激活可促进SS小鼠模型中的干眼症。具体的 AIM 3将研究人类原发性唾液的P2X7R和P2Y2R介导的促炎反应泪腺细胞和人类SS小唾液腺活检。该提案的成功完成将代表实现目标P2X7R和/或P2Y2R的最终目标的关键步骤 SS在人类中。