Mitochondrial dysfunction, metabolic syndrome and oxidative damage in Sjogren'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， 干眼症（即干燥性角结膜炎和口干症）以及泪腺和唾液腺减少 分泌物患有这种疾病的患者通常有这些外分泌腺的淋巴细胞浸润。系统性 表现是常见的，包括但不限于肺、皮肤、CNS、PNS的炎性疾病， 肾脏以及疲劳的病理水平。疲劳是干燥综合征的一个治疗不佳的方面， 一些病人将其描述为他们最严重的致残症状。疾病的病因还不清楚， 治疗主要是姑息性的。自由基介导的损伤、线粒体功能障碍和代谢 在干燥综合征中仅零星地研究了这些因素的相关性 还没有被研究过。干燥综合征的氧化损伤研究有限。我们将研究氧化 干燥综合征中应激、代谢综合征和线粒体功能障碍及其相互关系 我们的初步数据显示，在糖尿病患者中，氧化损伤和线粒体功能障碍显著增加。 这种疾病代谢综合征见于干燥综合征，与慢性低血糖密切相关。 水平炎症。但是，这三种疾病特征的相互作用和关联尚不清楚。 本项目的目标1将确定干燥综合征中的氧化损伤和线粒体功能障碍， 以及疾病中这些条件之间的联系。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。舍格伦的礼物 这是一个不同寻常的科学机会，因为受影响的器官会定期进行活检。因此，我们将研究两种外周 血液淋巴细胞以及从小唾液腺中纯化的淋巴细胞，我们正在进行的程序 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） 一组特征明确的舍格伦病患者。如果氧化损伤、线粒体 功能障碍和代谢综合征，然后确定一个亚组的干燥综合征患者与这些 这些特征可以允许在治疗上靶向特定患者。雷帕霉素和N-乙酰半胱氨酸 在系统性红斑狼疮（SLE）中的疗效。这两种分子都有利地影响线粒体 功能障碍FDA批准的N-乙酰半胱氨酸可改善SLE患者的疲劳。 Sjögren综合征的症状

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.