The long term objective of this application is to gain insight into the cellular and molecular controls of lacrimal secretion. The intent of the work is to provide a framework for understanding the pathogenesis of Sjogren's syndrome (SS) and for the development of therapies for dry-eye associated with the disease.
The specific aims of this application are designed to test three hypotheses that address 1) the relationship between early changes in the lacrimal gland and the later onset of autoimmune disease and 2) the identification of the cellular and molecular mechanisms that underlie the influence of the hormonal environment on the development and treatment of SS. The first specific aim will test the hypothesis that alterations in the expression or activity of G-protein coupled receptor (GPCR) signaling molecules occur prior to lymphocytic infiltration and result in disruptions in secretion that contribute to the lacrimal insufficiency of SS. Physiologic secretory function, cell-surface receptor-G protein coupling and mRNA and protein expression of G protein subunits, and relevant isoforms of adenylyl cyclase, phospholipase C and protein kinases will be evaluated in pre-autoimmune genetic models of SS and in control animals. The second specific aim will test the hypothesis that the autoimmune response in SS is, in part, precipitated by inappropriate Fas/Fas L mediated apoptosis of epithelial cells of the lacrimal gland.
The second aim will also test the hypothesis that the occurrence of apoptosis is influenced by the altered expression or activity of key GPCR signaling molecules.
The second aim will be accomplished by the evaluation of apoptosis in lacrimal epithelial cells of genetic models of SS prior to lymphocytic infiltration. The effect of activation or inhibition of GPCR signaling molecules on the occurrence of apoptotic figures and on the mRNA and protein expression of Fas, Fas L and bcl-2 family members will be measured. Alteration of the phosphorylation state of bcl-2 family members by these treatments will also be assessed. The final specific aim will test the hypothesis that the mechanism by which androgens maintain or restore lacrimal function is by influencing the expression or function of GPCR and/or programmed cell death signaling molecules. This will be tested by acute and chronic exposure of lacrimal acinar cells to androgen. Genomic and non-genomic effects of androgen on secretory function and on the expression and activity of signaling molecules will be assessed by similar methods used to accomplish the first and second specific aims.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY007380-11A2
Application #
6194631
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1987-04-01
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
11
Fiscal Year
2000
Total Cost
$277,869
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Physiology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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
Meneray, M A; Fields, T Y; Bennett, D J (2000) Gi/Go couple met-enkephalin to inhibition of cholinergic and beta-adrenergic stimulation of lacrimal secretion. Cornea 19:92-8
Meneray, M A; Bennett, D J (1998) Identification and characterization of G proteins in the mammalian lacrimal gland. Adv Exp Med Biol 438:197-203
Meneray, M A; Fields, T Y; Bennett, D J (1998) Gi2 and Gi3 couple met-enkephalin to inhibition of lacrimal secretion. Invest Ophthalmol Vis Sci 39:1339-45
Meneray, M A; Bennett, D J; Nguyen, D H et al. (1998) Effect of sensory denervation on the structure and physiologic responsiveness of rabbit lacrimal gland. Cornea 17:99-107
Meneray, M A; Fields, T Y (1998) G protein coupling of receptor activation to lacrimal secretion. Adv Exp Med Biol 438:133-8
Meneray, M A; Fields, T Y; Bennett, D J (1997) Gs and Gq/11 couple vasoactive intestinal peptide and cholinergic stimulation to lacrimal secretion. Invest Ophthalmol Vis Sci 38:1261-70
Meneray, M A; Bennett, D J (1995) Identification of G proteins in lacrimal gland. Invest Ophthalmol Vis Sci 36:1173-80
Meneray, M A; Fields, T Y; Bromberg, B B et al. (1994) Morphology and physiologic responsiveness of cultured rabbit lacrimal acini. Invest Ophthalmol Vis Sci 35:4144-58
Cripps, M M; Bennett, D J (1992) Pertussis-toxin insensitive enkephalin inhibition of adenylyl cyclase in lacrimal acinar cells. Life Sci 50:PL19-24

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