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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016985-05
Application #
7871339
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (93))
Program Officer
Shen, Grace L
Project Start
2006-08-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$313,381
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Xu, Shi; Ma, Linlin; Evans, Eunbyul et al. (2013) Polymeric immunoglobulin receptor traffics through two distinct apically targeted pathways in primary lacrimal gland acinar cells. J Cell Sci 126:2704-17
Xu, Shi; Olenyuk, Bogdan Z; Okamoto, Curtis T et al. (2013) Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv Drug Deliv Rev 65:121-38
Lu, Michael; Ding, Chuanqing (2012) CFTR-mediated Cl(-) transport in the acinar and duct cells of rabbit lacrimal gland. Curr Eye Res 37:671-7
Xu, Shi; Edman, Maria; Kothawala, Mubashera S et al. (2011) A Rab11a-enriched subapical membrane compartment regulates a cytoskeleton-dependent transcytotic pathway in secretory epithelial cells of the lacrimal gland. J Cell Sci 124:3503-14
Fazlollahi, Farnoosh; Sipos, Arnold; Kim, Yong Ho et al. (2011) Translocation of PEGylated quantum dots across rat alveolar epithelial cell monolayers. Int J Nanomedicine 6:2849-57
Li, Xiaodong; Wu, Kaijin; Edman, Maria et al. (2010) Increased expression of cathepsins and obesity-induced proinflammatory cytokines in lacrimal glands of male NOD mouse. Invest Ophthalmol Vis Sci 51:5019-29
Wu, Kaijin; Joffre, Corrine; Li, Xiaodong et al. (2009) Altered expression of genes functioning in lipid homeostasis is associated with lipid deposition in NOD mouse lacrimal gland. Exp Eye Res 89:319-32
Xie, Jiansong; Marchelletta, Ronald R; Thomas, Padmaja B et al. (2009) Transduced viral IL-10 is exocytosed from lacrimal acinar secretory vesicles in a myosin-dependent manner in response to carbachol. Exp Eye Res 88:467-78
Marchelletta, Ronald R; Jacobs, Damon T; Schechter, Joel E et al. (2008) The class V myosin motor, myosin 5c, localizes to mature secretory vesicles and facilitates exocytosis in lacrimal acini. Am J Physiol Cell Physiol 295:C13-28
Schenke-Layland, Katja; Xie, Jiansong; Angelis, Ekaterini et al. (2008) Increased degradation of extracellular matrix structures of lacrimal glands implicated in the pathogenesis of Sjogren's syndrome. Matrix Biol 27:53-66

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