BASAL/LATERAL--ENDOMEMBRANE TRAFFIC IN LACRIMAL ACINI

基底/侧部--泪腺腺泡中的内膜交通

• 批准号: 2888183
• 负责人: AUSTIN K MIRCHEFF
• 金额: $ 35.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2888183
• 关键词: Golgi apparatus; MHC class II antigen; Sjogren's syndrome; acinar cell; antigen presentation; apical membrane; autoantigens; autoimmune disorder; basolateral membrane; hormone regulation /control mechanism; immunocytochemistry; intracellular transport; keratoconjunctivitis sicca; laboratory rabbit; lacrimal apparatus; membrane permeability; protein transport; western blottings

Dry eye caused by lacrimal insufficiency is the most common form of ocular morbidity in the developed countries. It is caused by lymphocytic infiltration of the lacrimal glands in Sjogren s syndrome, which affects two million Americans, and in certain other immune system disorders. More subtle forms of lymphocytic infiltration may contribute to the secretory defect in primary lacrimal deficiency, which, like Sjogren s syndrome, occurs primarily in women. The thesis underlying this proposal is that the feature of lacrimal secretory epithelial cell function which causes them to provoke autoimmune responses is a previously little-appreciated recycling traffic between endomembrane compartments and the basal-lateral membrane (BLM), i.e., the membrane domain that contacts the interstitium. This traffic secretes immunomodulatory factors and potential auto antigens into the interstitium, and when cells have been induced to express major histocompatibility complex Class II molecules (MHC II), it allows them to present autoantigens in the same way that professional antigen presenting cells present foreign antigens. A further premise is that the normal spectra of secreted and displayed autoantigens are subject to peripheral tolerance, but that tolerance is overcome when changes in the BLM - endomembrane traffic perturb the autoantigenic spectra. Preliminary data indicate that such changes occur during sustained secretomotor stimulation, an experimental situation that may mimic the in vivo operation of the ocular surface - lacrimal gland feedback loop working to compensate for hormonally-induced glandular atrophy. Therefore, this project will combine methods of subcellular fractionation analysis that are uniquely capable of resolving compartments of the BLM -endomembrane traffic with widely used immunocytochemical methods to: 1) Delineate pathways between defined compartments of the BLM - endomembrane traffic. 2) Map the traffic of MHC II, of the La antigen, which is a prominent target of autoimmune reactions in Sjogren s syndrome, and of other potential autoantigens. 3) Investigate mechanisms responsible for stimulation-induced acceleration of BLM - endomembrane traffic. 4) Investigate mechanisms responsible for the stimulation-induced changes in targeting and/or segregation that cause Golgi and lysosomal proteins to enter the BLM pathway.

由泪液分泌不足引起的干眼症是眼部疾病的最常见形式。 发达国家的发病率。 它是由淋巴细胞 干燥综合征的泪腺浸润， 200万美国人，以及某些其他免疫系统疾病。 更 淋巴细胞浸润的微妙形式可能有助于分泌 原发性泪液缺乏症，像干燥综合征， 主要发生在女性身上。 这一建议的论点是， 泪腺分泌上皮细胞功能特点 它们引发自身免疫反应是一种以前很少被重视的 内膜间室和基底-侧膜间室之间的再循环运输 膜（BLM），即，与氚接触的膜结构域。 这种运输分泌免疫调节因子和潜在的自身抗原 当细胞被诱导表达主要的 组织相容性复合物II类分子（MHC II），它允许它们 呈递自身抗原的方式与专职抗原呈递 细胞呈递外来抗原。另一个前提是， 分泌和展示的自身抗原的光谱受到外周血淋巴细胞的影响。 但是，当BLM发生变化时，这种宽容就会被克服。 内膜运输扰乱了自身抗原谱。 初步数据 表明这种变化发生在持续分泌运动期间， 刺激，一种可以模拟体内 眼表面泪腺反馈回路的操作， 弥补尿道引起的腺体萎缩因此本 该项目将联合收割机结合亚细胞分离分析方法， 唯一能够分辨BLM内膜的隔室 交通与广泛使用的免疫细胞化学方法：1）描绘 BLM -内膜运输的定义区室之间的途径。 2)绘制MHCII和La抗原的运输图， 干燥综合征自身免疫反应靶点，以及其他 潜在的自身抗原3)调查对下列行为负责的机制 BLM -内膜运输的刺激诱导的加速。四、 研究负责刺激诱导的变化的机制， 靶向和/或分离，导致高尔基体和溶酶体蛋白， 进入BLM通道。