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.

干燥综合征是一种慢性炎症性自身免疫性疾病，临床特征为口干和 干眼（即干燥性角结膜炎和口干症）以及泪腺和唾液腺减少 分泌。患有这种疾病的患者的这些外分泌腺通常有淋巴细胞浸润。系统性 表现很常见，包括但不限于肺部、皮肤、中枢神经系统、PNS、 肾脏以及病理水平的疲劳。疲劳是干燥综合征的一个未得到很好治疗的方面， 一些患者将其描述为最令他们丧失能力的症状。疾病的病因尚不十分清楚， 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 仅在干燥综合征中进行了零星的研究以及这些因素的关联 还没有研究过。关于干燥综合征氧化损伤的研究有限。我们将研究氧化 压力、代谢综合征和线粒体功能障碍及其在干燥综合征中的相互关系。 我们的初步数据显示，氧化损伤和线粒体功能障碍显着增加 这种疾病。代谢综合征见于干燥综合征，与慢性低血压密切相关。 级炎症。但是，该疾病的这三个特征之间的相互作用和关联尚不清楚。 该项目的目标 1 将确定干燥综合征中的氧化损伤和线粒体功能障碍： 以及疾病中这些病症之间的关联。我们将使用技术来研究 线粒体功能障碍和氧化损伤可应用于淋巴细胞。 Sjögren's 推出了 这是一个不寻常的科学机会，因为定期对受影响的器官进行活检。因此，我们将研究外围设备 血液淋巴细胞以及从小唾液腺纯化的淋巴细胞，这是我们正在使用的程序 非常熟悉。目标 2 将确定代谢综合征是否与以下任一或两者相关 线粒体功能障碍和自由基损伤。这些研究将利用我们的大型 (n>400) 一组特征明确的干燥病患者。如果氧化损伤之间存在相关性，线粒体 功能障碍和代谢综合征，然后确定患有这些疾病的干燥综合征患者亚组 特征可能允许针对特定患者进行治疗。雷帕霉素3和N-乙酰半胱氨酸4具有 对系统性红斑狼疮（SLE）的疗效。这两种分子都有利地影响线粒体 功能障碍。 N-乙酰半胱氨酸经 FDA 批准，可改善 SLE 患者的疲劳。4,5 疲劳是一种治疗效果不佳的药物 干燥综合征的一个方面。