Trafficking of plgR in Lacrimal Gland

泪液蛋白维持角膜的健康，使眼表免受感染。泪液蛋白的主要来源是泪腺腺泡细胞。泪液中存在的主要抗体是二聚体IgA (dlgA)，它与上皮细胞基底外膜上的聚合免疫球蛋白A受体（plgR）相关。内化受体转胞到顶质膜，配体结合结构域从跨膜结构域分裂出来，并作为分泌组分- dlga复合物（称为slgA）释放到外液中。顶端plgR的外部结构域也会发生分裂，释放出游离分泌成分（SC）到外部分泌物中。尽管泪液中游离SC和slgA的浓度在体内是最高的，但关于泪腺中plgR运输和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MDCK细胞等模型系统中所描述的简单的转细胞途径之外的其他步骤。具体来说，我们发现泪腺中细胞plgR的一个组成部分是针对成熟分泌囊中积累的调节分泌（merocrine）途径的。我们假设这个plgR池将SC贡献到泪液中，代表了一个在以前研究的模型中未见的独特途径。我们进一步提出，mercrine效应物rabSD在plgR向分泌囊泡的分选和调控中起关键作用，并且该通路的消融将对眼表完整性和免疫产生不利影响。最后，我们提出plgR的缺失会对泪腺腺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产生不利影响。目标是：目的：检测泪腺腺泡细胞释放的SC和slgA是否来源于分离在不同分泌池中的plgR。目标2。检测外分泌抗体（rabSD）是否调节plgR的分选和SC的释放。目标3。目的：探讨plgR对维持泪腺功能和角膜完整性是否必要。

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.