Aging and Oxidative Stress Influence Salivary Gland Disease in Sjogren's Syndrome

衰老和氧化应激对干燥综合征唾液腺疾病的影响

• 批准号: 10682148
• 负责人: Umesh S Deshmukh
• 金额: $ 50.47万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682148
• 关键词: Address; Affect; Age; Aging; Animal Model; Antibodies; Appearance; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Big Data; Biological Models; Cells; Chronic; Circulation; Clinical; Color; Complement; Complex; Conjunctival Epithelium; Country; Data; Development; Diagnosis; Disease; Dryness; Ductal Epithelial Cell; Enzymes; Epithelial Cells; Female; Flow Cytometry; Fluids and Secretions; Free Radicals; Frequencies; Functional disorder; Genetic; Genetic Predisposition to Disease; Gland; Goals; Hyperactivity; Immune; Immune response; Immune system; Individual; Inflammatory Response; Injury; Knockout Mice; Lacrimal gland structure; Link; Literature; Location; Macrophage; Mediating; Mitochondria; Modality; Modeling; Mus; Oral; Organ; Outcome; Oxidative Stress; Oxidative Stress Induction; Pathway interactions; Patients; Phenotype; Population; Predisposition; Process; Production; Proteomics; Publishing; Recovery; Reporting; Respiration; Risk Factors; Role; SOD2 gene; Saliva; Salivary Gland Diseases; Salivary Glands; Sialadenitis; Sjogren' s Syndrome; Superoxides; Symptoms; Testing; Tissues; Work; Xerostomia; body system; cell injury; digital; expectation; eye dryness; human old age (65+); in vivo; innovation; mouse model; novel; novel therapeutic intervention; older patient; reduce symptoms; sex; symptom treatment; systemic autoimmune disease; tool; trait

Sjögren’s Syndrome (SS) is a chronic and debilitating systemic autoimmune disorder afflicting multiple organ systems. The targeting of the exocrine salivary and lacrimal glands by an autoimmune and inflammatory response leads to organ dysfunction causing reduced fluid secretion, which manifests into the dry mouth and dry eye symptoms of the disorder. Although a wide age range is reported in patients at diagnosis, it is well known that most SS patients are older. Why phenotypic traits are more prominent in older patients is unknown. Aging organs show heightened oxidative stress, which is often associated with declining organ function. Although,. SS patients show evidence of increased oxidative stress markers; whether elevated oxidative stress is causative or the outcome of an inflammatory response is unclear and challenging to investigate in patients. Hence based on published literature and our preliminary data, this proposal will test the overall hypothesis that the combined effects of autoimmunity and aging-associated oxidative stress contribute to salivary gland disease and dysfunction in SS. Aim 1 of this proposal will specifically address the hypothesis that aging-associated oxidative stress makes salivary glands more susceptible to immune-mediated damage. And in aim 2, by using a novel mouse model system, we will test the hypothesis that oxidative stress per se in salivary gland epithelial cells is insufficient to cause SS. The primary goal of this proposal is to understand the mechanisms behind key clinical observations in SS patients: prominence of clinical symptoms at an older age and the possible role of elevated oxidative stress in the disease process. Understanding basic mechanisms linking aging with organ dysfunction in SS will be essential in developing novel modalities to treat the disease.

舍格伦综合征（SS）是一种慢性和衰弱性全身性自身免疫性疾病， 器官系统。靶向外分泌唾液腺和泪腺的自身免疫和 炎症反应导致器官功能障碍，引起液体分泌减少，这表现为 进入该疾病的口干和干眼症症状。尽管据报道， 在诊断时，众所周知，大多数SS患者年龄较大。为什么表型性状 在老年患者中的作用尚不清楚。衰老的器官显示出更高的氧化应激，这通常是 与器官功能下降有关不过，。SS患者表现出氧化性增加的证据， 应激标志物;氧化应激升高是否是炎症反应的原因或结果 反应尚不清楚，在患者中进行研究具有挑战性。因此，根据已发表的文献， 我们的初步数据，这项建议将测试的整体假设， 自身免疫和衰老相关的氧化应激导致唾液腺疾病， SS功能障碍。本提案的目标1将具体阐述以下假设： 氧化应激使唾液腺更容易受到免疫介导的损伤。在目标2中， 通过使用一种新的小鼠模型系统，我们将检验唾液中氧化应激本身 腺上皮细胞不足以引起SS。本提案的主要目标是了解 SS患者关键临床观察背后的机制： 老年和氧化应激升高在疾病过程中的可能作用。理解 将SS中衰老与器官功能障碍联系起来的基本机制将是开发新的 治疗疾病的方法。