The lacrimal gland is of critical importance to good vision. Lacrimal gland secretions, including fluid and proteins, are responsible for maintaining the optical surface of the cornea, protecting the cornea from pathogens, and conveying growth factors to the cornea, which may help to maintain the cellular structure of the ocular surface. Activation of the secretory function of the lacrimal gland is under neural control. However, it is the hypothesis of this proposal that the sensory (afferent) innervation of the cornea is the primary neural input, which activates a secretomotor circuit comprising central and peripheral autonomic pathways. Moreover, the secondary hypothesis is that the intact neural circuit is critical to the maintenance of one of the most important cellular functions of the lacrimal gland, i.e., protein translation. After eliminating sensory activation and using differential display of message, preliminary experiments have pointed to the biochemical deficit as a decrease in message and activity of a kinase, elF2alpha, which controls the initiation of protein translation. Subsequent studies have shown that although basal and reflex tears are decreased, the lacrimal gland reveals elevated secretory responses to pharmacological stimulation. The massive accumulations of secretory granules seen after this ablation will be examined after removal or blockade of the parasympathetic innervation of the lacrimal gland. Other components of the translation process will also be examined, as will the ability of the lacrimal gland to translate messages for growth factors and secreted proteins. It is hypothesized that this unregulated translational activity will affect the production of transcription factors and the translation of unstable message. The proposed studies will demonstrate the innervational influences on the initiation of protein translation and will seek to understand the role of some key components of the MAP kinase cell signaling pathways, such as Ras. Finally, it is suggested that abnormalities of the innervational status of the lacrimal gland may be a key factor in the pathogenesis of dry eye disease and the changes seen in tear protein production in aging.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY012416-01
Application #
2752319
Study Section
Special Emphasis Panel (ZRG1-VISB (01))
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Toshida, Hiroshi; Nguyen, Doan H; Beuerman, Roger W et al. (2009) Neurologic evaluation of acute lacrimomimetic effect of cyclosporine in an experimental rabbit dry eye model. Invest Ophthalmol Vis Sci 50:2736-41
Toshida, Hiroshi; Nguyen, Doan H; Beuerman, Roger W et al. (2007) Evaluation of novel dry eye model: preganglionic parasympathetic denervation in rabbit. Invest Ophthalmol Vis Sci 48:4468-75
Nguyen, Doan H; Vadlamudi, Venu; Toshida, Hiroshi et al. (2006) Loss of parasympathetic innervation leads to sustained expression of pro-inflammatory genes in the rat lacrimal gland. Auton Neurosci 124:81-9
Nguyen, Doan H; Beuerman, Roger W; Meneray, Michele et al. (2006) Sensory denervation modulates eIF-2 alpha kinase expression in the rabbit lacrimal gland. Curr Eye Res 31:287-95
Nguyen, Doan H; Toshida, Hiroshi; Schurr, Jill et al. (2004) Microarray analysis of the rat lacrimal gland following the loss of parasympathetic control of secretion. Physiol Genomics 18:108-18
Zhou, L; Huang, L Q; Beuerman, R W et al. (2004) Proteomic analysis of human tears: defensin expression after ocular surface surgery. J Proteome Res 3:410-6
Zhou, Lei; Beuerman, Roger W; Barathi, Amutha et al. (2003) Analysis of rabbit tear proteins by high-pressure liquid chromatography/electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom 17:401-12
Toshida, Hiroshi; Beuerman, Roger W (2002) Effects of preganglionic parasympathetic denervation on the rabbit lacrimation. Adv Exp Med Biol 506:225-9
Nguyen, Doan H; Beuerman, Roger W; Toshida, Hiroshi (2002) The effects of sensory and parasympathetic denervation on the kinases and initiation factors controlling protein synthesis in the lacrimal gland. Adv Exp Med Biol 506:65-70
Toshida, Hiroshi; Nakata, Katsuhiko; Hamano, Takashi et al. (2002) Effect of gefarnate on the ocular surface in squirrel monkeys. Cornea 21:292-9

Showing the most recent 10 out of 13 publications