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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要干燥综合征是一种自身免疫性疾病，会导致慢性炎症和损伤/功能障碍唾液腺和泪腺分泌减少是本病的主要临床表现之一。损害了 400 万美国人（其中大部分是女性）的口腔和全身健康，且无法治愈或有效生物疗法对干燥病有很大希望，但慢性自身免疫病却有很大希望。炎症极大地阻碍了成功的可能性，迫切需要新的策略和方法。减轻自身免疫性炎症，实现受损和持续有效的再生该探索性项目的目的是阐明专门的亲唾液腺功能障碍的影响。解决介质（SPM）对唾液腺干的扩张、更新和免疫调节活性的影响 SPM 是体外和体内细胞的促溶解脂质介质，可介导脂质的主动溶解。炎症并已被证明具有增强免疫调节、促愈合和再生的能力此外，我们的初步研究表明，SPM 也可以由干细胞产生。确凿的证据表明 SPM 对干细胞活性和免疫调节特性产生积极影响我们创新的中心假设是 SPM 可以促进可持续发展。通过作用于干燥病环境中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炎症并增强组织再生在目标 1 中，我们将研究 lipoxin A4 和 maresin-1 是否可以增强组织再生。唾液更新、扩张、唾液类器官形成、SPM 产生和免疫调节活性来自正常 C57BL/6 小鼠的腺体干细胞，在基于基质胶的扩增和分化培养系统中。目标2，我们将确定这些SPM是否可以促进受损唾液的结构和功能恢复具体来说，我们将评估 lipoxin A4 和 maresin-1 是否在体内调节干燥症的情况。给移植了唾液腺干细胞的干燥病小鼠注射可以同时减轻炎症并增强组织再生，从而实现可持续的结构和功能该项目采用的主要方法包括基质胶培养、体内培养。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 测定的完成将阐明这一创新的探索性项目。 SPM 在干燥病唾液腺干细胞介导的组织再生中的作用。将促进干细胞疗法的发展，同时减轻自身免疫炎症和增强组织再生，实现干燥症唾液腺可持续有效的恢复综合征患者以及患有其他唾液腺损伤/炎症状况的患者。