BASAL/LATERAL--ENDOMEMBRANE TRAFFIC IN LACRIMAL ACINI

基底/侧部--泪腺腺泡中的内膜交通

• 批准号: 2684500
• 负责人: AUSTIN K MIRCHEFF
• 金额: $ 31.16万
• 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/2684500
• 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.

泪腺功能不全引起的干眼症是最常见的眼病形式 发达国家的发病率。 这是淋巴细胞引起的 干燥综合征中泪腺的浸润，影响 200 万美国人，以及某些其他免疫系统疾病。 更多的 淋巴细胞浸润的微妙形式可能有助于分泌 原发性泪腺缺乏症的缺陷，与干燥综合征一样， 主要发生于女性。 该提案的论点是 泪腺分泌上皮细胞功能的特点导致 它们激发自身免疫反应的作用以前很少受到重视 内膜室和基底外侧之间的循环交通 膜（BLM），即接触间质的膜域。 这种交通分泌免疫调节因子和潜在的自身抗原 进入间质，当细胞被诱导表达主要 组织相容性复合物 II 类分子 (MHC II)，它使它们能够 以与专业抗原呈递相同的方式呈递自身抗原 细胞呈递外来抗原。进一步的前提是，正常情况下 分泌和显示的自身抗原的光谱受外周 容忍度，但是当 BLM 发生变化时，这种容忍度就会被克服 - 内膜交通扰乱自身抗原谱。 初步数据 表明这种变化发生在持续的分泌运动过程中 刺激，一种可以模拟体内环境的实验情况 眼表的运作 - 泪腺反馈回路的作用 补偿激素引起的腺体萎缩。因此，这 该项目将结合亚细胞分级分析方法 具有独特的能力来解析 BLM 内膜的区室 使用广泛使用的免疫细胞化学方法进行交通：1) 描绘 BLM 的定义区室之间的通路 - 内膜交通。 2) 绘制 La 抗原 MHC II 的交通图，这是一个突出的 干燥综合征和其他自身免疫反应的目标 潜在的自身抗原。 3）调查负责的机制 刺激引起的 BLM - 内膜交通加速。 4） 研究刺激引起的变化的机制 导致高尔基体和溶酶体蛋白的靶向和/或分离 进入BLM途径。