Trafficking of plgR in Lacrimal Gland

泪腺中 plgR 的贩运

• 批准号: 7643156
• 负责人: Sarah F Hamm-Alvarez
• 金额: $ 31.65万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643156
• 关键词: Ablation; Acinar Cell; Adenoviruses; Adverse effects; Affect; Antibodies; Apical; Binding; Biological; Biological Assay; Biological Models; Cell Line; Cell membrane; Cholinergic Agonists; Cleaved cell; Co-Immunoprecipitations; Complex; Cornea; Data; Epithelial Cells; Eukaryotic Cell; Extracellular Domain; Family; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Immunity; Immunofluorescence Immunologic; Immunoglobulin A; In Vitro; Infection; Investigation; Kinetics; Lacrimal gland structure; Lactoferrin; Ligand Binding Domain; Liquid substance; MDCK cell; Maintenance; Membrane; Membrane Protein Traffic; Modeling; Molecular; Muramidase; Mus; Oryctolagus cuniculus; Pathway interactions; Physiological; Play; Predisposition; Proteins; Regulation; Role; Route; Secretory Component; Secretory Vesicles; Sorting - Cell Movement; Source; Study models; System; Testing; basolateral membrane; lacrimal; lacrimal acini; novel; ocular surface; pathogen; receptor; response; tear proteins; trafficking

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.

描述：撕裂蛋白保持角膜的健康状况，并使眼表面保持不感染。撕裂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侧膜上的聚合物免疫球蛋白A受体（PLGR）相关。内部化受体被转移到顶端质膜，其中配体结合结构域与跨膜跨膜结构域裂解，并释放到外部流体中，作为分泌组件-DLGA复合物称为SLGA。也可能会发生顶端PLGR外部域的切割，将自由分泌组件（SC）释放到外部分泌物中。尽管自由SC和SLGA以浓度在体内最高的浓度中流泪，但几乎没有关于PLGR运输和SC和SC和/或SLGA释放的机制几乎一无所知。我们在兔富富腺泡细胞中的初步数据表明，PLGR的分泌贩运涉及超出模型系统（例如MDCK细胞）中描述的简单跨性途径的其他步骤。具体而言，我们发现泪acini中细胞PLGR的成分针对受调节的分泌（Merocrine）途径，用于在成熟的分泌囊泡中积累。我们假设该PLGR池在泪水中贡献了SC，代表了以前研究的模型中未见的独特途径。我们进一步提出，美分泌效应子RABSD在PLGR对分泌囊泡的分类和调节中起关键作用，并且该途径的消融将对眼部表面完整性和免疫力产生不利影响。最后，我们提出，PLGR的丧失将对富富富集糖脂的组织和功能产生不利影响，同时也对眼表面完整性和免疫力产生不利影响。目的是：目标1。测试从泪腺腺泡细胞中释放出的SC和SLGA是否源自在不同分泌池中隔离的PLGR。目的2。测试外分泌的RAB，RABSD是否调节PLGR的排序和SC从Merocrine池的释放。目标3。测试PLGR是否对于维持泪腺功能和角膜完整性是否至关重要。