Mitochondrial dysfunction, metabolic syndrome and oxidative damage in Sjogren's Syndrome

干燥综合征中的线粒体功能障碍、代谢综合征和氧化损伤

• 批准号: 9387723
• 负责人: Robert Hal Scofield
• 金额: $ 19.7万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387723
• 关键词: Acetylcysteine; Affect; Autoimmune Diseases; Biopsy; CD4 Positive T Lymphocytes; Cells; Central Nervous System Diseases; Characteristics; Chronic; Clinical; Data; Disease; Etiology; Exocrine Glands; FDA approved; FRAP1 gene; Fatigue; Free Radicals; Generations; Gland; Immune; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Keratoconjunctivitis Sicca; Kidney Diseases; Lacrimal gland structure; Lymphocyte; Mediating; Metabolic; Metabolic syndrome; Minor salivary gland structure; Mitochondria; Organ; Oxidative Stress; Pathogenicity; Pathologic; Patients; Peripheral Blood Lymphocyte; Peripheral Nervous System Diseases; Procedures; Salivary; Salivary Glands; Sjogren' s Syndrome; Subgroup; Systemic Lupus Erythematosus; Techniques; Therapeutic; Xerostomia; cohort; disabling symptom; eye dryness; free radical oxygen; improved; inflammatory lung disease; mitochondrial dysfunction; oxidative damage; palliative; skin disorder

Sjögren's syndrome is a chronic inflammatory, autoimmune disorder characterized clinically by dry mouth and dry eye (that is, keratoconjunctivitis sicca and xerostomia) as well as diminished lacrimal and salivary gland secretion. Patients with this condition routinely have lymphocytic infiltration of these exocrine glands. Systemic manifestations are common, including, but not limited to, inflammatory disease of the lungs, skin, CNS, PNS, kidneys as well as pathological levels of fatigue. Fatigue is a poorly treated facet of Sjögren's syndrome and some patients describe it as their most disabling symptom. Disease etiology is not well understood and treatment is mainly palliative. Free radical mediated damage, mitochondrial dysfunction and metabolic syndrome have been investigated only sporadically in Sjögren's syndrome and associations of these factors have not been studied. Studies of oxidative damage in Sjögren's syndrome are limited. We will study oxidative stress, metabolic syndrome and mitochondrial dysfunction and their inter-relationship in Sjögren's syndrome. Our preliminary data shows significantly increased oxidative damage as well as mitochondrial dysfunction in the disease. Metabolic syndrome is found in Sjögren's syndrome and is closely associated with chronic low level inflammation. But, the interaction and association of these three features of the illness are not known. Aim 1 of this project will determine oxidative damage and mitochondrial dysfunction in Sjögren's syndrome as well as the association between these conditions in the disease. We will use techniques for study of mitochondrial dysfunction and oxidative damage that can be applied to lymphocytes. Sjögren's presents an unusually scientific opportunity in that affected organs are routinely biopsied. So, we will study both peripheral blood lymphocytes as well as lymphocytes purified from minor salivary glands, a procedure with which we are highly familiar. Aim 2 will determine whether metabolic syndrome is correlated with either or both of mitochondrial dysfunction and free radical damage. These studies will take advantage of our large (n>400) cohort of well characterized Sjögren's patients. If there is correlation among oxidative damage, mitochondrial dysfunction and metabolic syndrome, then identifying a subgroup of Sjögren's syndrome patients with these characteristics may allow targeting of specific patients therapeutically. Rapamycin3 and N-acetylcysteine4 have efficacy in systemic lupus erythematosus (SLE). Both these molecules favorably affect mitochondrial dysfunction. N-acetylcysteine, which is FDA-approved, improved fatigue in SLE.4,5 Fatigue is a poorly treated facet of Sjögren's syndrome.

Sjögren综合征是一种慢性炎症性自身免疫性疾病，其特征在临床上以干口干和 干眼症（即圆锥角膜炎和静脉炎）以及泪腺和唾液腺减少 分泌。患有这种情况的患者通常会淋巴细胞浸润。系统性 表现很常见，包括但不限于肺，皮肤，CNS，PNS， 肾脏以及疲劳的病理水平。疲劳是Sjögren综合征和 一些患者将其描述为最残疾的症状。疾病病因尚不清楚， 治疗主要是姑息治疗。自由基介导的损伤，线粒体功能障碍和代谢 综合征仅在Sjögren综合征中偶尔研究和这些因素的关联 尚未研究。 Sjögren综合征中氧化损伤的研究受到限制。我们将研究氧化剂 压力，代谢综合征和线粒体功能障碍及其在Sjögren综合征中的相互关系。 我们的初步数据显示，氧化损伤显着增加，线粒体功能障碍 疾病。代谢综合征在Sjögren综合征中发现，与慢性低相关 水平炎症。但是，尚不清楚这三个疾病特征的相互作用和关联。 该项目的目标1将确定Sjögren综合征中的氧化损伤和线粒体功能障碍 以及这些疾病中这些疾病之间的关联。我们将使用技术进行研究 线粒体功能障碍和可应用于淋巴细胞的氧化损伤。 Sjögren的礼物 经常被活检的受影响器官的异常科学机会。因此，我们将研究两个外围 血液淋巴细胞以及从小唾液腺纯化的淋巴细胞，我们是我们的过程 AIM 2将确定代谢综合征是否与任何一个或两个相关 线粒体功能障碍和自由基损害。这些研究将利用我们的大型（n> 400） Sjögren患者的特征良好。如果氧化物损伤之间存在相关性，则线粒体 功能障碍和代谢综合征，然后确定Sjögren综合征患者的亚组 特征可以允许特定患者对特定患者进行治疗。雷帕霉素3和n-乙酰半胱氨酸具有 全身性红斑狼疮（SLE）的功效。这两个分子都受到有利影响线粒体 功能障碍。 N-乙酰半胱氨酸是FDA批准的，SLE的疲劳改善了。4,5疲劳是一种处理良好的 Sjögren综合征的方面。