Glycolytic metabolites, Calcium entry and Sjogren’s syndrome

糖酵解代谢物、钙进入和干燥综合征

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要唾液对于维持口腔健康至关重要，据估计超过 500 万人在口腔中美国患有唾液腺功能障碍（pSS），这是一种自身免疫性疾病。病因不明且多种因素在发病机制中发挥作用的疾病重要的是，浸润性免疫细胞（尤其是 Th17 细胞）、产生自身抗体的 B 细胞和研究表明，pSS 患者的唾液腺中大量存在树突状细胞，但其机制并不明确。尽管 Ca2+ 已被证明发挥着重要作用，但为什么这些免疫细胞存在于唾液组织中尚不清楚。在调节唾液分泌以及免疫细胞激活中发挥核心作用，有关调节 pSS 中 Ca2+ 通道活性的机制尚不清楚。例如乳酸，以前被认为是细胞代谢的废物，但最近它已被认为是细胞代谢的废物。研究表明，这些代谢物可有效调节免疫反应，抑制 T 细胞。运动性阻止 T 细胞运动、从发炎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该水平，重要的是，增加。乳酸水平对于抑制 STIM1 迁移至关重要，从而阻止 Ca2+ 进入唾液腺导致 ER Ca2+ 水平降低并诱导 ER 应激的细胞。压力会释放警报素，这对于 T/B 细胞激活及其迁移到唾液组织至关重要。最后，乳酸介导的 Orai1 活性丧失导致 IFNα 和 IL-17 细胞因子的过量产生来自 CD4+ T 细胞并抑制对代谢重编程很重要的线粒体功能 T 细胞转换所需的该资助的目的是阐明其机制。内源性代谢物，例如乳酸，会调节 Ca2+ 信号传导并导致唾液腺功能障碍。该应用基于乳酸通过抑制 Ca2+ 进入而诱导自身免疫的假设导致唾液分泌减少和氧化磷酸化抑制的通道。我们的研究结果有望为内源代谢物在细胞中的作用提供新的见解。调节Ca2+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将有助于更好地了解这些事件。对于阐明唾液腺功能障碍的新疗法非常重要。