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

控制干燥综合征的自身免疫炎症并促进唾液腺再生

• 批准号: 10657745
• 负责人: Qing Yu
• 金额: $ 29.85万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657745
• 关键词: Acceleration; Advanced Development; Affect; American; Anabolism; Anti-Inflammatory Agents; Apoptosis; Attenuated; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Bioinformatics; Biological Assay; Biological Response Modifier Therapy; Biological Response Modifiers; C57BL/6 Mouse; CD59 Antigen; Cell Culture Techniques; Cells; Chronic; Clinical; Development; Disease; Flow Cytometry; Functional disorder; Health; Hematoxylin and Eosin Staining Method; High-Throughput RNA Sequencing; Homeostasis; Immune; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Innate Immune Response; Knowledge; Lacrimal gland structure; Leucocytic infiltrate; Lipoxins; Mediating; Mediator; Methodology; Methods; Mus; Natural regeneration; Omega-3 Fatty Acids; Oral; Organ; Organoids; Pathway interactions; Patients; Polyunsaturated Fatty Acids; Population; Process; Production; Proliferating; Property; Resolution; Salivary; Salivary Glands; Signal Transduction; Sjogren' s Syndrome; Stains; Stem cell transplant; Structure; System; T-Lymphocyte; Time; Tissue Stains; Tissues; Transplantation; Woman; Xerostomia; adaptive immune response; arachidonate; attenuation; autoimmune inflammation; chemokine; cytokine; draining lymph node; eye dryness; functional restoration; healing; immunoregulation; improved; in vivo; inhibitor; innovation; insight; lipid mediator; lipoxin A4; matrigel; mouse model; novel; receptor; regenerative; regenerative therapy; restoration; stem cell therapy; stem cells; stemness; success; tissue regeneration; transcriptomics

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.

项目摘要 干燥综合征是一种自身免疫性疾病，其引起慢性炎症和免疫系统的损伤/功能障碍。 唾液腺和泪腺，以少涎为主要临床表现之一。疾病大大 损害了400万美国人的口腔和全身健康，其中大部分是女性，没有治愈或有效的治疗方法。 生物疗法干细胞疗法对干燥综合症有很大的希望，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 为了减弱自身免疫性炎症， 功能失调的唾液腺这个探索性项目的目的是阐明专业化的亲， 解析介质（SPM）对唾液腺干的扩展、更新和免疫调节活性的影响 细胞在体外和体内。SPM是促消退脂质介质，其介导 炎症，并已证明能够增强免疫调节，促愈合和再生 干细胞的特性。此外，SPM也可以由干细胞产生。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。我们的创新中心假设是，SPM可以促进可持续发展， 通过作用于两个部位来恢复干燥综合征患者受损唾液腺的结构和功能 唾液腺干细胞和免疫/炎性细胞同时减轻自身免疫性炎症 增强组织再生在目标1中，我们将检查脂氧素A4和maresin-1是否可以促进 更新、扩增、唾液类器官形成、SPM产生和唾液的免疫调节活性 在基于Matrigel的扩增和分化培养系统中来自正常C57 BL/6小鼠的腺干细胞。在 目的2：研究这些自组织微粒是否能促进受损唾液腺的结构和功能的恢复 腺在干燥病的条件下在体内。具体而言，我们将评估脂氧素A4和maresin-1是否 给患有干燥综合症的小鼠移植唾液腺干细胞， 减轻炎症并增强组织再生，从而实现可持续的结构和功能 修复唾液腺。该项目中采用的主要方法包括基质胶培养， 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qPCR， 免疫组织化学和Luminex测定。这一创新探索项目的完成将阐明 Sjögren病中SPM在唾液腺干细胞介导的组织再生中的作用。它 将促进干细胞疗法的发展，同时减轻自身免疫性炎症， 促进组织再生，以实现干燥症唾液腺的可持续和有效恢复 综合征患者以及患有其他唾液腺损伤/炎性病症的患者。