Dry eye (DE), and one of its major forms - chronic posterior blepharitis (CPB) - is a widespread multifactorial disease that diminishes the quality of life of millions of people, especially elderly, women, and those who live in adverse climates, by impairing their vision. Up to 30% of the general population is affected by DE. No effective treatment for DE exists at present with the only FDA-approved drug for treating DE and CPB, Restasis(R), having a therapeutic effect in 15% of patients vs. 5% in the placebo group. The disease is linked to changes in the very thin lipid- and protein rich ocular surface structure called tear film (TF). The long-term goals of our project are: 1) to redefine the biochemical composition and 3-D structure of TF, and 2) to determine the major biochemical and biophysical factors that stabilize or destabilize TF and hence those components important for the development of CPB and DE in general. Our general hypotheses are that: 1) the lipid composition of TF is more elaborate than previously thought;2) the TF structure is stabilized due to very specific lipid/lipid and lipid/protein interactions;and, 3) TF is not quite liquid but instead has either a liquid crystal-like, or a gel-like structure and is composed of gradually intercalating layers and zones enriched with particular types of molecules and supramolecular complexes.
The aims of the project are as follows.
Aim 1. To challenge the current views on the biochemical composition of human TF as formed primarily of MGS by comparatively characterizing the lipids of MGS and AT, determining the lipid components of TF and their likely sources, and identifying and evaluating the roles of the critical lipid components in the formation and maintaining of TF.
Aim 2. To test the hypothesis that normal TF is not quite liquid but instead has an either liquid crystal-like or a gel- like dynamic nanostructure composed of gradually intercalating layers and zones enriched with particular types of molecules and supramolecular complexes which is stabilized by ionic and hydrophilic/hydrophobic interactions between lipids, proteins, and other molecules and whose structure is susceptible to changes due to alterations in its lipid and protein compositions, tear osmolality, ocular temperature, mixing, environmental factors, etc.
Aim 3. To determine whether or not there are cyclic qualitative and quantitative changes in human AT lipids and MGS that could be associated with the cyclic increase of DE symptoms and TF instability in CPB patients compared with normal subjects.

Public Health Relevance

Dry eye syndrome (DE) in general, and one of its major forms - chronic posterior blepharitis (CPB) - is a wide- spread condition that severely deteriorates the quality of life of millions of people by impairing their vision. No effective treatment for DE exists at present with the only FDA approved prescription drug for treating CPB, Restasis(R), having a therapeutic effect in 15% of patients vs. 5% in the placebo group. The disease is related to abnormal changes in lipids and proteins in the preocular tear film (TF). The goal of the project is to investigate the biochemical changes in lipid composition of human aqueous tears and meibomian gland secretions and the corresponding biophysical changes in TF that occur in CPB in order to uncover their mechanisms and develop more effective diagnostic tests and treatments of this condition.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019480-04
Application #
8435505
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$289,621
Indirect Cost
$80,773
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
McMahon, Anne; Lu, Hua; Butovich, Igor A (2014) A role for ELOVL4 in the mouse meibomian gland and sebocyte cell biology. Invest Ophthalmol Vis Sci 55:2832-40
Butovich, Igor A; Lu, Hua; McMahon, Anne et al. (2014) Biophysical and morphological evaluation of human normal and dry eye meibum using hot stage polarized light microscopy. Invest Ophthalmol Vis Sci 55:87-101
Wojtowicz, Jadwiga C; Butovich, Igor A; McMahon, Anne et al. (2014) Time-dependent degenerative transformations in the lipidome of chalazia. Exp Eye Res 127:261-9
Arciniega, Juan C; Uchiyama, Eduardo; Butovich, Igor A (2013) Disruption and destabilization of meibomian lipid films caused by increasing amounts of ceramides and cholesterol. Invest Ophthalmol Vis Sci 54:1352-60
McMahon, Anne; Lu, Hua; Butovich, Igor A (2013) The spectrophotometric sulfo-phospho-vanillin assessment of total lipids in human meibomian gland secretions. Lipids 48:513-25
Lu, Hua; Wojtowicz, Jadwiga C; Butovich, Igor A (2013) Differential scanning calorimetric evaluation of human meibomian gland secretions and model lipid mixtures: transition temperatures and cooperativity of melting. Chem Phys Lipids 170-171:55-64
Butovich, Igor A (2013) Tear film lipids. Exp Eye Res 117:4-27
Butovich, Igor A; Arciniega, Juan C; Lu, Hua et al. (2012) Evaluation and quantitation of intact wax esters of human meibum by gas-liquid chromatography-ion trap mass spectrometry. Invest Ophthalmol Vis Sci 53:3766-81
Butovich, Igor A (2011) On the presence of (O-acyl)-omega-hydroxy fatty acids and of their esters in human meibomian gland secretions. Invest Ophthalmol Vis Sci 52:639-41
Arciniega, Juan C; Nadji, Erfan J; Butovich, Igor A (2011) Effects of free fatty acids on meibomian lipid films. Exp Eye Res 93:452-9

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