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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

Sjögren's综合征（SS）是一种慢性且令人衰弱的系统性自身免疫性疾病器官系统。通过自身免疫和炎症反应导致器官功能障碍导致流体分泌减少，这表现进入疾病的干嘴和干眼症状。虽然报告了很广的年龄范围诊断患者，众所周知，大多数SS患者都年龄较大。为什么表型特征更多在老年患者中突出的是未知的。衰老器官表现出加剧的氧化应激，通常是与器官功能下降相关。尽管如此， SS患者显示出氧化增加的证据压力标记；氧化应激升高是病因还是炎症的结果反应尚不清楚，并且在患者中进行调查。因此，基于出版的文献和我们的初步数据，该提案将检验总体假设，即自身免疫性和与衰老相关的氧化应激有助于唾液腺疾病和 SS中的功能障碍。本提案的目标1将特别解决与衰老相关的假设氧化应激使唾液网格更容易受到免疫介导的损伤。在AIM 2中，通过使用新型的小鼠模型系统，我们将测试以下假设。腺上皮细胞不足以引起SS。该提议的主要目标是了解 SS患者关键临床观察背后的机制：临床症状的突出年龄较大，氧化应激率在疾病过程中的可能作用。理解 SS中将衰老与器官功能障碍联系起来的基本机制对于发展新颖治疗疾病的方式。