Intermittent fasting restores salivary gland function in Sjögren’s syndrome

干燥综合征(SS)是一种影响数百万美国人的慢性自身免疫性疾病，其中 唾液腺是自身反应性T细胞的主要靶点，导致淋巴功能低下，主要 疾病的标志。口干会引起各种口腔健康问题，严重 影响生活质量。SS无法治愈，目前的治疗主要是姑息治疗。失败 SS的治疗方法与无法控制自身炎症密不可分；因此，我们建议 同时对两者进行调查。为了实现可持续的唾液分泌，发展 同时促进内源性唾液腺再生和保护腺体的途径 防止自身免疫性炎症造成的进一步伤害是迫切需要的。我们的初步研究 强烈提示间歇性禁食(IF)对SS有保护作用。在非- 肥胖糖尿病(NOD)小鼠是SS的一种明确的自发模型，IF促进了 唾液腺干细胞，并上调Wnt和Notch信号和过氧化物酶体增殖物- 激活的受体驱动的脂肪酸氧化，这是关键参与扩张和 多种干细胞类型的分化。它还缓解了自身反应性T辅助分子1、T辅助分子17和 涎腺引流淋巴结内的细胞毒性T细胞反应。这项提议的目标是 该项目是确定IF对内源性唾液活动的影响，这是以前未曾探索过的 腺体干/祖细胞与SS自身免疫性炎症关系的研究 和IF益处的细胞机制，长期目标是开发有效和有针对性的 从根本上改善唾液腺功能的疗法。基于文献和我们的初步研究 结果，我们提出了中心假设，即IF对唾液腺起到有益的作用。 促进内源性唾液腺再生和减少T细胞介导的修复 SS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，我们将剖析IF影响细胞增殖和增殖的潜在分子机制。 自发SS模型NOD小鼠唾液腺干细胞的分化；在目标2中， 我们将评估IF对导管涎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细胞的衰减 唾液组织中的自身免疫性炎症，使用谱系追踪的小鼠模型和可诱导的 SS的模型。这项研究的成功完成将为发展 治疗SS样外分泌病的有效新疗法，以及对 由辐射、药物或衰老引起的口干症和其他自身免疫性疾病 其发病机制与SS相似。

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.