Trafficking of plgR in Lacrimal Gland

描述：泪液蛋白维持角膜的健康，并保持眼表免受感染。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伊加（dlgA），其与上皮细胞基底外侧膜处的多聚免疫球蛋白A受体（plgR）缔合。内化的受体被转胞吞至顶端质膜，其中配体结合结构域从跨膜结构域裂解并作为称为slgA的分泌组分-dlgA复合物释放到外部流体中。顶端plgR的外部结构域的切割也可以发生，将游离分泌组分（SC）释放到外部分泌物中。尽管游离SC和slgA以体内最高的浓度存在于泪液中，但对于涉及泪腺中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的分泌运输涉及超出模型系统如MDCK细胞中描绘的简单胞吞途径的额外步骤。具体地，我们已经发现，泪腺泡中的细胞plgR的组分靶向调节分泌（局部分泌）途径，以在成熟分泌囊泡中积累。我们假设该plgR池有助于SC进入泪液，代表了在先前研究的模型中未观察到的独特途径。我们进一步提出，部分分泌效应，rabSD，在plgR的分选和调节分泌囊泡中起着关键作用，并且该途径的消融将对眼表面完整性和免疫力产生不利影响。最后，我们提出plgR的损失将不利地影响泪腺泡局部分泌途径的组织和功能，同时也不利地影响眼表面完整性和免疫力。目标是：目标1。为了测试从泪腺腺泡细胞释放的SC和slgA是否来源于隔离在不同分泌池中的plgR。目标二。为了测试外分泌分泌rab，rabSD，是否调节plgR的分选和SC从部分分泌池的释放。目标3：测试plgR是否对维持泪腺功能和角膜完整性至关重要。

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.