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: 10213312
• 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/10213312
• 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; Periodicity; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; 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; base; 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; 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.

Sjögren’s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