Trafficking of plgR in Lacrimal Gland

描述：泪液蛋白维持角膜的健康，使眼表不受感染。泪液蛋白质的主要来源是泪腺腺泡细胞。泪液中的主要抗体是二聚体免疫球蛋白A(DlgA)，它与上皮细胞基侧膜上的聚合免疫球蛋白A受体(PlgR)有关。内化的受体被跨细胞转运到顶端质膜，在那里配体结合结构域被从跨膜结构域中切割出来，释放到外部液体中，形成分泌成分-dlgA复合体，称为SLGA。顶端plgR的外区也可以发生裂解，释放游离的分泌成分(SC)到外部分泌物中。虽然游离SC和SLGA在泪液中的浓度是体内最高的，但关于plgR运输和泪腺中SC和/或SLGA释放的机制几乎一无所知。我们在兔泪腺泡细胞中的初步数据表明，plgR的分泌运输涉及到比模型系统(如MDCK细胞)中描述的简单的跨细胞途径更多的步骤。具体地说，我们发现泪腺泡中细胞plgR的一部分靶向于调节的分泌(分分泌)途径，以便在成熟的分泌囊中积累。我们假设这个plgR池使SC流泪，这代表了一种以前研究的模型中没有看到的独特途径。我们进一步认为，内分泌效应因子RabSD在plgR对分泌性囊泡的分选和调节中起关键作用，而这一途径的消融将对眼表完整性和免疫功能产生不利影响。最后，我们认为plgR的缺失将对泪腺腺泡细胞分泌通路的组织和功能产生不利影响，同时也会对眼表完整性和免疫力产生不利影响。目的：1.检测泪腺腺泡细胞释放的SC和SLGA是否来源于不同分泌池中的plgR。目的2.检测外分泌Rab，rabSD是否调节plgR的分选和SC从内分泌池中的释放。目的3.检测plgR是否对维持泪腺功能和角膜完整性是必需的。

DESCRIPTION: Tear proteins maintain the health of the cornea and keep the ocular surface free of infection. The major source of tear proteins is the lacrimal gland acinar cell. The major antibody present in tears is dimeric IgA (dlgA), which associates with the polymeric immunoglobulin A receptor (plgR) at epithelial cell basolateral membranes. The internalized receptor is transcytosed to the apical plasma membrane, where the ligand- binding domain is cleaved from the membrane-spanning domain and released into external fluid as the secretory component-dlgA complex termed slgA. Cleavage of the external domain of apical plgR can also occur, releasing free secretory component (SC) into external secretions. Although free SC and slgA are present in tears at concentrations among the highest in the body, almost nothing is known about the mechanisms involved in plgR trafficking and SC and/or slgA release in the lacrimal gland. Our preliminary data in rabbit lacrimal acinar cells suggests that the secretory trafficking of plgR involves additional steps beyond the simple transcytotic pathways delineated in model systems such as MDCK cells. Specifically, we have found that a component of cellular plgR in lacrimal acini is targeted to the regulated secretory (merocrine) pathway for accumulation in mature secretory vesicles. We hypothesize that this plgR pool contributes SC into tears, representing a unique pathway not seen in previously-studied models. We further propose that the merocrine effector, rabSD, plays a key role in the sorting and regulation of plgR to secretory vesicles, and that ablation of this pathway will have adverse effects on ocular surface integrity and immunity. Finally, we propose that loss of plgR will adversely affect the organization and function of the lacrimal acinar merocrine pathways, while also adversely affecting ocular surface integrity and immunity. The aims are: Aim 1. To test whether SC and slgA released from lacrimal gland acinar cells are derived from plgR sequestered in distinct secretory pools. Aim 2. To test whether the exocrine secretory rab, rabSD, regulates sorting of plgR and release of SC from the merocrine pool. Aim 3. To test whether plgR is essential for maintenance of lacrimal gland functions and corneal integrity.