The preocular tear film plays an essential role in maintaining ocular surface integrity, protecting against microbial challenge and preserving visual acuity. Tear film dysfunction, in turn, may severely impact the eye and lead to desiccation, ulceration and perforation of the cornea, an increased incidence of infectious disease, and pronounced visual impairment and blindness. Countless people suffer from tear film disorders, which are termed dry eye syndromes and are classified into 2 major types: aqueous-deficient and evaporative. Aqueous- deficient dry eye is due to decreased tear secretion from the lacrimal gland. An example is Sj?gren's syndrome (SS), a common autoimmune disease that afflicts primarily women and destroys the lacrimal gland. Evaporative dry eye is typically caused by meibomian gland dysfunction and may be a major cause of dry eye during menopause, use of estrogen replacement therapy and aging. The long range objectives of this grant application are to test our hypotheses that: (1) sex steroids are extremely important in the physiological regulation of the ocular surface and adnexa, as well as the production of the tear film;and (2) sex, sex steroid hormones, and in particular androgen deficiency, are critical etiologic factors in the pathogenesis of both aqueous-deficient and evaporative dry eye syndromes. Experimental procedures include mouse models, whole genome microarrays (e.g. gene chips), real-time-PCR, cell cultures, immunoassays, 2D gels, enzyme assays, histology, image analysis and hormone reconstitution experiments.
Our specific aims are to: (1) determine the mechanisms by which sex and sex steroids influence the normal and SS lacrimal gland;(2) unravel the processes underling the sex and sex steroid effects on the meibomian gland;and (3) explore the role of sex and sex steroids in the control of boundary lubrication and surfactant proteins at the ocular surface and/or adnexa. Results from these studies should significantly advance our understanding of the processes by which sex and sex steroids influence the anterior segment of the eye. In addition, findings may have health relatedness for the eye, because they: (1) explore the regulation of the tear film;and (2) may lead to the development of specific therapies for the clinical treatment of dry eye syndromes.

Public Health Relevance

Dry eye syndrome is one of the leading causes of patient visits to eye care practitioners, as well as an important public health problem that has no cure. This disease afflicts over 30 milllion Americans, predominantly women, and significantly impacts their quality of life. We propose to determine why dry eye occurs primarily in women and to translate our research results into the development of new and unique therapeutic strategies to treat aqueous-deficient and evaporative dry eye.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005612-28
Application #
8581344
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1985-09-30
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
28
Fiscal Year
2014
Total Cost
$624,439
Indirect Cost
$302,563
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
Liu, Yang; Kam, Wendy R; Ding, Juan et al. (2014) Effect of azithromycin on lipid accumulation in immortalized human meibomian gland epithelial cells. JAMA Ophthalmol 132:226-8
Rahimi Darabad, Raheleh; Suzuki, Tomo; Richards, Stephen M et al. (2014) Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice? Exp Eye Res 127:153-60
Liu, Yang; Kam, Wendy R; Ding, Juan et al. (2014) One man's poison is another man's meat: using azithromycin-induced phospholipidosis to promote ocular surface health. Toxicology 320:1-5
Ding, Juan; Sullivan, David A (2014) The effects of insulin-like growth factor 1 and growth hormone on human meibomian gland epithelial cells. JAMA Ophthalmol 132:593-9
Schmidt, Tannin A; Sullivan, David A; Knop, Erich et al. (2013) Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface. JAMA Ophthalmol 131:766-76
Ding, Juan; Kam, Wendy R; Dieckow, Julia et al. (2013) The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Invest Ophthalmol Vis Sci 54:4341-50
Darabad, Raheleh Rahimi; Suzuki, Tomo; Richards, Stephen M et al. (2013) Influence of aromatase absence on the gene expression and histology of the mouse meibomian gland. Invest Ophthalmol Vis Sci 54:987-98
Knop, Erich; Knop, Nadja; Millar, Thomas et al. (2011) The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci 52:1938-78
Nichols, Kelly K; Foulks, Gary N; Bron, Anthony J et al. (2011) The international workshop on meibomian gland dysfunction: executive summary. Invest Ophthalmol Vis Sci 52:1922-9
Richards, Stephen M; Sullivan, David A (2009) Do Genetic Alterations in Sex Steroid Receptors Contribute to Lacrimal Gland Disease in Sjogren's Syndrome? Open Endocrinol J 3:5-11

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