Biochemistry and Biophysics of the Preocular Tear Film

Summary

Principal Investigator: Igor A Butovich
Affiliation: University of Texas Southwestern Medical Center
Country: USA
Abstract: 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.
Funding Period: ----------------2010 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. pmc A role for ELOVL4 in the mouse meibomian gland and sebocyte cell biology
    Anne McMahon
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
    Invest Ophthalmol Vis Sci 55:2832-40. 2014
  2. pmc Biophysical and morphological evaluation of human normal and dry eye meibum using hot stage polarized light microscopy
    Igor A Butovich
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas
    Invest Ophthalmol Vis Sci 55:87-101. 2014
  3. pmc Tear film lipids
    Igor A Butovich
    Department of Ophthalmology and the Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, USA Electronic address
    Exp Eye Res 117:4-27. 2013
  4. pmc Differential scanning calorimetric evaluation of human meibomian gland secretions and model lipid mixtures: transition temperatures and cooperativity of melting
    Hua Lu
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, United States
    Chem Phys Lipids 170:55-64. 2013
  5. pmc The spectrophotometric sulfo-phospho-vanillin assessment of total lipids in human meibomian gland secretions
    Anne McMahon
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9057, USA
    Lipids 48:513-25. 2013
  6. pmc Disruption and destabilization of meibomian lipid films caused by increasing amounts of ceramides and cholesterol
    Juan C Arciniega
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9057, USA
    Invest Ophthalmol Vis Sci 54:1352-60. 2013
  7. pmc Toward an animal model of the human tear film: biochemical comparison of the mouse, canine, rabbit, and human meibomian lipidomes
    Igor A Butovich
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Invest Ophthalmol Vis Sci 53:6881-96. 2012
  8. pmc Comparative HPLC-MS analysis of canine and human meibomian lipidomes: many similarities, a few differences
    Igor A Butovich
    University of Texas Southwestern Medical Center, Department of Ophthalmology and the Graduate School of Biomedical Sciences, Dallas, TX, USA
    Sci Rep 1:24. 2011
  9. pmc Effects of free fatty acids on meibomian lipid films
    Juan C Arciniega
    Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, TX 75390 9057, USA
    Exp Eye Res 93:452-9. 2011
  10. pmc Evaluation and quantitation of intact wax esters of human meibum by gas-liquid chromatography-ion trap mass spectrometry
    Igor A Butovich
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9057, USA
    Invest Ophthalmol Vis Sci 53:3766-81. 2012

Scientific Experts

Detail Information

Publications17

  1. pmc A role for ELOVL4 in the mouse meibomian gland and sebocyte cell biology
    Anne McMahon
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
    Invest Ophthalmol Vis Sci 55:2832-40. 2014
    ..We investigated whether Stgd3 mice, harboring mutations in ELOVL4 that have been shown to decrease the levels of its biosynthetic lipid products, would represent a model system in which to define the role of such lipids in meibum...
  2. pmc Biophysical and morphological evaluation of human normal and dry eye meibum using hot stage polarized light microscopy
    Igor A Butovich
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas
    Invest Ophthalmol Vis Sci 55:87-101. 2014
    ..To study melting characteristics and the morphology of human and mouse meibum...
  3. pmc Tear film lipids
    Igor A Butovich
    Department of Ophthalmology and the Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, USA Electronic address
    Exp Eye Res 117:4-27. 2013
    ..A map of the meibomian lipidome (as it is seen in reverse phase liquid chromatography/mass spectrometry experiments) is presented. Directions of future efforts in the area are outlined. ..
  4. pmc Differential scanning calorimetric evaluation of human meibomian gland secretions and model lipid mixtures: transition temperatures and cooperativity of melting
    Hua Lu
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, United States
    Chem Phys Lipids 170:55-64. 2013
    ..The highly asymmetrical shape of the thermotropic peak of meibum is important for the physiology and biophysics of TFLL...
  5. pmc The spectrophotometric sulfo-phospho-vanillin assessment of total lipids in human meibomian gland secretions
    Anne McMahon
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9057, USA
    Lipids 48:513-25. 2013
    ..The SPV method can also be adopted for analyzing other types of complex lipids secretions, such as sebum, as well as whole lipid extracts from other lipid-enriched organs and tissues, if proper standards are chosen...
  6. pmc Disruption and destabilization of meibomian lipid films caused by increasing amounts of ceramides and cholesterol
    Juan C Arciniega
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9057, USA
    Invest Ophthalmol Vis Sci 54:1352-60. 2013
    ..We evaluated quantitatively direct effects of ceramide (Cer) and free cholesterol (FC) on meibomian lipid films (MLF) using a Langmuir trough (LT) and a Brewster angle microscope (BAM)...
  7. pmc Toward an animal model of the human tear film: biochemical comparison of the mouse, canine, rabbit, and human meibomian lipidomes
    Igor A Butovich
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Invest Ophthalmol Vis Sci 53:6881-96. 2012
    ....
  8. pmc Comparative HPLC-MS analysis of canine and human meibomian lipidomes: many similarities, a few differences
    Igor A Butovich
    University of Texas Southwestern Medical Center, Department of Ophthalmology and the Graduate School of Biomedical Sciences, Dallas, TX, USA
    Sci Rep 1:24. 2011
    ..The lipidomes of cMGS and hMGS were found to be qualitatively similar, which implies similar biosynthetic and biodegradation pathways in canines and humans. However, some quantitative differences between the two were observed...
  9. pmc Effects of free fatty acids on meibomian lipid films
    Juan C Arciniega
    Department of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, TX 75390 9057, USA
    Exp Eye Res 93:452-9. 2011
    ....
  10. pmc Evaluation and quantitation of intact wax esters of human meibum by gas-liquid chromatography-ion trap mass spectrometry
    Igor A Butovich
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9057, USA
    Invest Ophthalmol Vis Sci 53:3766-81. 2012
    ..Their complete characterization on the level of individual intact lipid species has not been completed yet. We obtained detailed structural information on previously uncharacterized meibomian WE...
  11. pmc Lipidomics of human Meibomian gland secretions: Chemistry, biophysics, and physiological role of Meibomian lipids
    Igor A Butovich
    Department of Ophthalmology and the Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9057, USA
    Prog Lipid Res 50:278-301. 2011
    ..It is concluded that despite a substantial progress in the area of Meibomian glands lipidomics, there are large areas of uncertainty that need to be addressed in future experiments...
  12. pmc Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice
    Anne McMahon
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    J Lipid Res 52:1128-38. 2011
    ..In addition to the skin, Elovl4 is also expressed in other tissues, including the retina, brain, and testes. Thus, these mice will facilitate future studies to define the roles of C28-C36 fatty acids in the Elovl4-expressing tissues...
  13. pmc Meibomian lipid films and the impact of temperature
    Igor A Butovich
    Department of Ophthalmology, Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9057, USA
    Invest Ophthalmol Vis Sci 51:5508-18. 2010
    ..This may have a detrimental impact on the stability and functionality of the human tear film and the tear film lipid layer. The goal of this project was to quantitatively examine the possible impact of temperature on the latter...
  14. pmc Fatty acid composition of cholesteryl esters of human meibomian gland secretions
    Igor A Butovich
    Department of Ophthalmology and the Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
    Steroids 75:726-33. 2010
    ..We conclude that the FA composition of CE can be successfully established in LC-MS experiments conducted in NIM. Meibomian CE have a large presence of both saturated and unsaturated FA with an average molar ratio of 4 to 1, respectively...