Glycolytic metabolites, Calcium entry and Sjogren’s syndrome

糖酵解代谢物、钙进入和干燥综合征

• 批准号: 10706579
• 负责人: Brij B Singh
• 金额: $ 56.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706579
• 关键词: Acinar Cell; Affect; American; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Back; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcium; Cell Death; Cell physiology; Cells; Collaborations; Dendritic Cells; Development; Disease; Etiology; Event; Fatigue; Functional disorder; Grant; IL17 gene; Immune; Immune response; Immune system; Immunophenotyping; Inflammation; Inflammatory; Lactation; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Movement; Oral health; Oxidative Phosphorylation; Pathogenesis; Patients; Persons; Phenotype; Play; Production; Research; Role; STIM1 gene; Saliva; Salivary; Salivary Glands; Signal Transduction; Site; Sjogren' s Syndrome; Stimulus; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Waste Products; age related; cell motility; cytokine; endoplasmic reticulum stress; functional restoration; immune activation; immune cell infiltrate; immunoregulation; insight; lymphoid structures; migration; mouse model; novel; novel therapeutics; prevent; saliva secretion; salivary acinar cell; therapeutically effective; uptake

Project Summary Saliva is essential for maintaining oral health and it has been estimated that more than 5 million people in the US suffers from salivary gland dysfunctions. Primary Sjögren's syndrome (pSS) is an autoimmune disease with unknown etiology and multiple factors have been suggested to play a role in the pathogenesis of pSS. Importantly, infiltrating immune cells (especially Th17 cells), autoantibodies producing B cells, and dendritic cells are shown to be highly present in salivary glands of pSS patients; however, the mechanism as why these immune cells are present in salivary tissues is not known. Although Ca2+ is shown to play a central role in regulating saliva secretion as well as in immune cell activation, information regarding the mechanism that modulate Ca2+ channel activity in pSS is not well understood. Endogenous metabolite, such as lactate was previously considered as a waste product of cellular metabolism, but recently it has been shown that these metabolites effectively modulate the immune response. L-lactate inhibit T cell motility thereby preventing the movement of T cells, back from the inflamed tissues and increase in lactate levels are observed in the salivary glands of pSS mouse models and in pSS patients. Importantly, increase in lactate levels were critical in inhibiting STIM1 migration thereby preventing Ca2+ entry in salivary gland cells that lead to a decrease in ER Ca2+ levels and induced ER stress. Lactate-mediated induction of ER stress releases alarmins that is essential for T/B cell activation and their migration into salivary tissues. Finally, lactate-mediated loss of Orai1 activity resulted in the overproduction of IFN and IL-17 cytokines from CD4+ T cells and inhibited mitochondrial function that was important for metabolic reprograming needed for T cell switching. The objective of this grant is to elucidate the mechanism(s) thereby endogenous metabolites, such as lactate modulates Ca2+ signaling and leads to salivary gland dysfunction. This application is based on the hypothesis that lactate induces autoimmunity by inhibiting Ca2+ entry channels which results in decreased saliva secretion and suppression of the oxidative phosphorylation. The results of our studies are expected to provide new insights into the role of endogenous metabolites in regulating Ca2+ channels and the molecular mechanism involved in salivary gland dysfunction as well as establish ways to restore functional salivary glands. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions.

项目摘要 唾液对维持口腔健康至关重要，据估计， 美国人患有唾液腺功能障碍。原发性干燥综合征（pSS）是一种自身免疫性疾病， 病因不明的疾病和多种因素已被认为在发病机制中发挥作用 的pSS。重要的是，浸润性免疫细胞（尤其是Th 17细胞）、产生自身抗体的B细胞和 树突状细胞在pSS患者的唾液腺中高度存在;然而， 至于为什么这些免疫细胞存在于唾液组织中还不清楚。虽然Ca 2+被证明是一个 在调节唾液分泌以及免疫细胞活化中的中心作用， 调节pSS中Ca 2+通道活性的机制还不清楚。内源性代谢物， 如乳酸盐以前被认为是细胞代谢的废物，但最近它已 已经证明这些代谢物有效地调节免疫反应。L-乳酸抑制T细胞 运动，从而防止T细胞的运动，从发炎的组织返回，并增加乳酸 在pSS小鼠模型和pSS患者的唾液腺中观察到水平。重要的是，增加 乳酸水平在抑制STIM 1迁移从而阻止唾液腺中的Ca 2+进入中是关键的 导致ER Ca 2+水平降低并诱导ER应激的细胞。乳酸介导的ER诱导 应激释放对T/B细胞活化及其迁移到唾液组织中必不可少的alarmin。 最后，乳酸盐介导的Orai 1活性丧失导致IFN γ和IL-17细胞因子的过度产生 从CD 4 + T细胞和抑制线粒体功能，这是重要的代谢重编程 T细胞转换所必需的。这项补助金的目的是阐明机制， 内源性代谢物如乳酸调节Ca 2+信号传导并导致唾液腺功能障碍。 本申请基于乳酸盐通过抑制Ca 2+进入诱导自身免疫的假设 通道，导致唾液分泌减少和氧化磷酸化抑制。 我们的研究结果有望为内源性代谢物在 调节Ca 2+通道和参与唾液腺功能障碍的分子机制以及 建立恢复唾液腺功能的方法。对这些事件的更多了解将是 在阐明唾液腺功能障碍的新疗法中具有重要意义。