Intermittent fasting restores salivary gland function in Sjögren’s syndrome

间歇性禁食可恢复干燥综合征患者的唾液腺功能

• 批准号: 10561670
• 负责人: Jing Zhou
• 金额: $ 47.26万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-03 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561670
• 关键词: Acinar Cell; Affect; Aging; American; Autoimmune; Autoimmune Diseases; Cell Compartmentation; Cells; Characteristics; Clinical; Complex; Cytotoxic T-Lymphocytes; Data; Development; Disease; Duct (organ) structure; Equilibrium; Exhibits; FOXP3 gene; Face; Food deprivation (experimental); Gene Expression Profile; Genes; Genetic Engineering; Gland; Goals; Grant; High-Throughput RNA Sequencing; Immune; Inbred NOD Mice; Inflammation; Inflammatory; Injury; Intermittent fasting; Link; Literature; Mediating; Modeling; Molecular; Mouse Strains; Mus; Natural regeneration; Oral health; Palliative Care; Pathogenesis; Pathway interactions; Periodicals; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Proliferating; Quality of life; Radiation; Regenerative capacity; Regimen; Regulation; Reporting; Saliva; Salivary; Salivary Glands; Salivary duct structure; Serum; Signal Transduction; Sjogren' s Syndrome; Source; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Treatment Failure; Water; Xerostomia; attenuation; autoimmune inflammation; autoimmune pathogenesis; autoinflammation; autoreactive T cell; autoreactivity; cell type; chronic autoimmune disease; draining lymph node; effective therapy; fatty acid oxidation; immunoregulation; improved; insight; mouse model; new therapeutic target; notch protein; novel therapeutics; palliative; prevent; progenitor; regenerative; response; restoration; saliva secretion; stem cell based approach; stem cells; targeted treatment; tissue regeneration

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting millions of Americans, in which salivary glands are the primary target of autoreactive T cells, leading to hyposalivation, the major disease hallmark. Hyposalivation (dry mouth) causes a variety of oral health issues and severely compromises quality of life. SS has no cure and current treatments are predominantly palliative. Failure of therapies for SS are inextricably linked to the inability to control autoinflammation; thus, we propose to investigate both simultaneously. To achieve sustainable salivary secretion, development of approaches to simultaneously enhance endogenous salivary gland regeneration and protect the glands from further injury from autoimmune inflammation are critically needed. Our preliminary studies strongly suggest that there are protective actions provided by intermittent fasting (IF) in SS. In non- obese diabetic (NOD) mice, a well-defined spontaneous model of SS, IF enhances the proliferation of salivary gland stem cells, and upregulates Wnt and Notch signaling and Peroxisome Proliferator- Activated Receptor-driven fatty acid oxidation, which are critically involved in the expansion and differentiation of multiple stem cell types. It also mitigates autoreactive T helper 1, T helper 17 and cytotoxic T cell responses in the salivary gland-draining lymph nodes. The objective of this proposed project is to determine the previously unexplored impact of IF on the activity of endogenous salivary gland stem/progenitor cells and autoimmune inflammation in SS to unravel the underlying molecular and cellular mechanisms of IF benefits, with the long-term goal of developing effective and targeted therapies to fundamentally improve salivary gland function. Based on the literature and our preliminary results, we formulated the central hypothesis that IF exerts beneficial actions on salivary gland restoration through promoting endogenous salivary gland regeneration and diminishing T cell mediated autoimmune inflammation in SS. This hypothesis will be tested through the following specific aims: In Aim 1, we will dissect the potential molecular mechanisms for the impact of IF on the proliferation and differentiation of salivary gland stem cells in the NOD mouse, a spontaneous model of SS; In Aim 2, we will assess the impact of IF on the self-expansion and cellular plasticity of ductal salivary gland progenitor cells and acinar cells, the function and plasticity of T cell subsets, and the attenuation of autoimmune inflammation in the salivary tissues, using lineage tracing mouse models and an inducible model of SS. Successful completion of this study will provide new targets for the development of effective new therapeutics for SS-like exocrinopathy, as well as provide insight into the treatment of xerostomia caused by radiation, medications or aging, and other autoimmune diseases that share similarities in their pathogenesis with SS.

干燥综合征（SS）是一种慢性自身免疫性疾病，影响数百万美国人，其中 唾液腺是自身反应性T细胞的主要靶点，导致唾液分泌减少， 疾病标志唾液过少（口干）会导致各种口腔健康问题， 会影响生活质量SS无法治愈，目前的治疗主要是姑息性的。失败 SS的治疗与无法控制自身炎症有着千丝万缕的联系;因此，我们建议 同时调查这两件事。为了实现可持续的唾液分泌， 同时增强内源性唾液腺再生和保护腺体的方法 从自身免疫性炎症的进一步损伤是迫切需要的。我们的初步研究 这强烈表明，间歇性禁食（IF）在SS中具有保护作用。在非- 肥胖糖尿病（NOD）小鼠，一种明确的自发性SS模型，IF增强了 唾液腺干细胞，并上调Wnt和Notch信号和过氧化物酶体激活剂- 激活受体驱动的脂肪酸氧化，这是关键参与的扩张和 多种干细胞类型的分化。它还减轻自身反应性T辅助细胞1，T辅助细胞17和 唾液腺引流淋巴结中的细胞毒性T细胞应答。建议的目标 该项目旨在确定IF对内源性唾液酸活性的先前未探索的影响， 腺干/祖细胞和自身免疫性炎症在SS中的作用 和IF效益的细胞机制，长期目标是开发有效的和有针对性的 从根本上改善唾液腺功能的疗法。根据文献和我们的初步研究， 结果，我们提出了中心假设，即IF对唾液腺发挥有益作用 通过促进内源性唾液腺再生和减少T细胞介导的 自身免疫性炎症。这一假设将通过以下具体目标进行检验： 目的1、探讨干扰素对肿瘤细胞增殖及凋亡的影响， NOD小鼠（SS的自发模型）中唾液腺干细胞的分化;在Aim 2中， 我们将评估IF对导管唾液腺的自我扩张和细胞可塑性的影响 祖细胞和腺泡细胞，T细胞亚群的功能和可塑性，以及T细胞亚群的衰减。 唾液组织中的自身免疫性炎症，使用谱系追踪小鼠模型和可诱导的 SS模型这项研究的成功完成将为发展 有效的新疗法SS样外分泌体病，以及提供深入了解治疗 由辐射，药物或衰老引起的口干症，以及其他自身免疫性疾病， 其发病机制与SS相似。