Controlling Autoimmune Inflammation and Promoting Salivary Gland Regeneration in Sjogren's Syndrome

项目总结 Sjӧgren综合征是一种自身免疫性疾病，可导致慢性炎症和 唾液腺和泪腺，以下垂为主要临床表现之一。这种病很严重 危害400万美国人的口腔和全身健康，其中大部分是女性，没有治愈或有效的方法 生物疗法。干细胞疗法有望治愈SjӧGren病，但慢性自身免疫性疾病 炎症极大地阻碍了成功的可能性。迫切需要新的战略和方法。 为了减轻自身免疫性炎症，实现受损和持续的有效再生 唾液腺功能失调。这一探索性项目的目的是阐明专门的亲子关系的影响 唾液腺干扩增、更新及免疫调节活性的解析介体 体外和体内的细胞。SPM是促进分解的脂质介体，介导主动分解 炎症，并表现出增强免疫调节，促进愈合和再生的能力 干细胞的特性。此外，干细胞也可以产生SPM。我们的初步研究提供了 令人信服的证据表明，SPM对干细胞活性和免疫调节特性都有积极影响 小鼠唾液腺干细胞。我们创新的中心假设是，可持续发展战略管理可以促进可持续发展 Sjӧ-gren病患者受损唾液腺的结构和功能恢复 唾液腺干细胞和免疫/炎症细胞同时减轻自身免疫性炎症 并促进组织再生。在目标1中，我们将研究脂氧素A4和MAREINE-1是否可以促进 唾液的更新、扩张、唾液类器官的形成、SPM的产生和免疫调节活性 正常C57BL/6小鼠腺干细胞在Matrigel扩增和分化培养系统中的表达。在……里面 目的2，我们将确定这些SPM是否能促进受损唾液的结构和功能的恢复 Sjӧ‘s病患者体内的腺体情况。具体地说，我们将评估脂氧素A4和MAREST-1 将唾液腺干细胞移植到Sjӧgren病小鼠体内，可以同时 消炎和促进组织再生，从而实现可持续的结构和功能 唾液腺的修复。在这个项目中使用的主要方法包括Matrigel文化，Intra- 唾液腺细胞转移、高通量RNA测序和生物信息学、流式细胞术、实时定量聚合酶链式反应、 免疫组织化学和Luminex法。这一创新探索项目的完成将阐明 SPM在干燥病条件下唾液腺干细胞介导的组织再生中的作用。它 将推动干细胞疗法的发展，同时减轻自身免疫性炎症和 促进组织再生，实现唾液腺的可持续有效修复 综合征患者以及其他唾液腺损伤/炎症情况的患者。

PROJECT SUMMARY Sjӧgren’s syndrome is an autoimmune disease that causes chronic inflammation and damage/dysfunction of salivary and lacrimal glands, with hyposalivation as one of the main clinical manifestations. The disease greatly compromises the oral and systemic health of 4 million Americans, mostly women, with no cure or effective biological therapy. Stem cell therapies hold great promise for Sjӧgren’s disease, but the chronic autoimmune inflammation greatly impedes the likelihood of success. There is a critical need for new strategies and methods for attenuation of autoimmune inflammation achieve effective and sustained regeneration of the damaged and dysfunctional salivary glands. The objective of this exploratory project to elucidate the impact of specialized pro- resolving mediators (SPMs) on the expansion, renewal and immune-regulatory activity of salivary gland stem cells both in vitro and in vivo. SPMs are pro-resolving lipid mediators that mediate active resolution of inflammation and have demonstrated abilities to enhance the immunomodulatory, pro-healing and regenerative properties of stem cells. Moreover, SPMs can also be produced by stem cells. Our preliminary studies provided compelling evidence that SPMs positively impact both the stem cell activity and the immune-regulatory property of mouse salivary gland stem cells. Our innovative central hypothesis is that SPMs can promote sustainable structural and functional restoration of damaged salivary glands in Sjӧgren’s disease setting by acting on both salivary gland stem cells and immune/inflammatory cells to simultaneously mitigate autoimmune inflammation and enhance tissue regeneration. In Aim 1, we will examine whether lipoxin A4 and maresin-1 can boost the renewal, expansion, salivary organoid formation, SPM production and immune-regulatory activity of salivary gland stem cells from normal C57BL/6 mice in Matrigel-based expansion and differentiation culture systems. In Aim 2, we will determine if these SPMs can promote the structural and functional restoration of damaged salivary glands in Sjӧgren’s disease condition in vivo. Specifically, we will assess whether lipoxin A4 and maresin-1 administered to Sjӧgren’s disease-afflicted mice transplanted with salivary gland stem cells can simultaneously attenuate inflammation and enhance tissue regeneration, thereby achieving sustainable structural and functional restoration of salivary glands. Major methodologies employed in this project include Matrigel culture, intra- salivary gland cell transfer, high-throughput RNA-sequencing and bioinformatics, flow cytometry, real-time qPCR, immunohistochemistry and Luminex assay. Completion of this innovative exploratory project will elucidate the actions of SPMs in salivary gland stem cell-mediated tissue regeneration in the Sjögren’s disease condition. It will advance the development of stem cell therapies that concomitantly attenuate autoimmune inflammation and enhance tissue regeneration to achieve sustainable and effective restoration of salivary glands for Sjögren’s syndrome patients as well as patients with other salivary gland injury/ inflammatory conditions.