Cornea, Ocular Surface, Meibomian Glands
Jack H. Skirball Endowed Research Chair.
Senior Scientific Investigator Award, Research to Prevent Blindness, Inc.
Association for Research in Vision and Ophthalmology Gold Fellow
Career Achievement Award, Ocular Toxicology, Society of Toxicology
The Ocular Surface, Laboratory Science Editor
Investigative Opthalmology & Visual Science, Editorial Board Member
Cutaneous and Ocular Toxicology, Editorial Board Member
Cornea, Editorial Board Member
National Eye Institute, Review Panel Member
Ocular Pathology, Doheny Eye Foundation, Los Angeles, California.
Experimental Ocular Pathology, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
Meibomian Gland Dysfunction
The long-term goal of this project is to understand the mechanism of age-related meibomian gland dysfunction (MGD) and evaporative Dry Eye. Recently we have shown that mouse and human meibomian glands undergo specific age-related changes including decreased acinar cell proliferation, acinar atrophy, and altered peroxisome proliferator-activated receptor gamma (PPAR gamma) localization from cytoplasmic-vesicluar/nuclear in young to nuclear in old mice and humans. Since PPAR is a lipid sensitive, nuclear receptor implicated in regulating adipocyte and sebocyte differentiation and lipogenesis, our findings suggest that PPAR may be involved in modulating meibomian gland differentiation during aging. Based on these findings we propose that aging of the meibomian gland may result in down-regulation of PPAR? leading to decreased meibocyte differentiation and lipid synthesis, gland atrophy, and a hyposecretory MGD. Currently, there is a MAJOR GAP in knowledge regarding the role of PPAR in meibomian gland function. To test this hypothesis we have develop novel imaging and cell culture systems to assess gland volume, lipid synthesis and their regulation by PPAR?. Using non-linear optical (NLO) microscopy and array tomography we have volumetrically reconstructed the mouse meibomian gland and measured total, cellular and lipid volumes in young and old glands. Preliminary studies suggest that atrophy of aging meibomian glands involves a marked loss in the lipid volume suggesting decreased meibocyte differentiation. Additionally, we have used coherent anti-stokes raman spectroscopy (CARS) to identify the regional lipid profiles within the meibomian gland and have tentatively shown that there is an age-related change in the maturation of meibomian gland lipids moving from the acini into the duct. Furthermore, we have developed an SV40 immortalized mouse meibocyte cell line that synthesizes lipids and expresses PPAR. Using these novel tools we propose the following Specific Aims. (1). Establish the age-related changes in PPAR localization and associated gene expression patterns by quantifying the subcellular localization, post-translational modification and downstream response gene expression patterns in the mouse and human meibomian gland. (2) Determine the effects of aging on the meibomian gland by quantifying the volume and lipid synthesis using NLO microscopy and array tomography to volumetrically reconstruct the meibomian gland and CARS to assess regional changes in lipid components present in the acini, ductule and duct of the mouse and human meibomian gland. (3) Assess the effects of natural and synthetic PPAR ligands on lipid synthesis by quantifying the subcellular localization, post-translational modification and downstream response gene expression patterns in cultured mouse meibocytes. (4) Measure the effect of PPAR ligands on meibocyte differentiation in vivo by quantifying the changes in PPAR expression, meibocyte proliferation, gland volume and lipid synthesis in young and old mouse meibomian glands.
Jester JV, Potma E, Brown DJ: PPAR? regulates mouse meibocyte differentiation and lipid synthesis. Ocular Surface 14:484-494, 2016.
Parfitt GJ, Lewis P, Young RD, Richardson A, Lyons JG, Di Girolamo N, Jester JV: Renewal of holocrine meibomian glands by label-retaining, uni-potent epithelial progenitors. Stem Cell Reports 7:399-410, 2016.
Mikula ER, Jester JV, Juhasz T: Measurement of an elasticity map in the human cornea. Invest Ophthalmol Vis Sci 57:3282-3286, 2016.
Parfitt GJ, Brown DJ, Jester JV: Transcriptome analysis of aging mouse meibomian glands. Mol Vis 22:518-527, 2016.
Jester JV, Morishige N, BenMohamed L, Brown DJ, Osorio N, Hsiang C, Perng GC, Jones C, Wechsler SL: Confocal microscopic analysis of a rabbit eye model of high incidence recurrent herpes stromal keratitis (HSK). Cornea 35: 81-88, 2016.
Jester JV, Parfitt GJ, Brown DJ: Meibomian Gland Dysfunction: Keratinization or Atrophy? BMC Ophthalmology 15(Suppl 1):156, 2015.
Parfitt GJ, Kavianpour B, Wu KL, Xie Y, Borwn DJ, Jester JV: Immunofluorescence tomography of mouse ocular surface epithelial stem cells and the their niche microenvironment. Invest Ophthalmol Vis Sci 56: 7338-7344. 2015.
Winkler M, Shoa G, Tran ST, Xie Y, Thomasy S, Raghunathan VK, Murphy D, Brown DJ, Jester JV: A comparative study of vertebrate corneal structure: The evolution of a refractive lens. Invest Ophthalmol Vis Sci 56: 2764-2772, 2015.
Quantock AJ, Winkler M, Parfitt GJ, Young RD, Brown DJ, Boote C, Jester JV: From nano to macro: Studying the hierarchical structure of the corneal extracellular matrix. Exp Eye Res 133: 81-99, 2015.
Parfitt GJ, Geyfman M, Xie Y, Jester JV: Characterization of quiescent epithelial cells in mouse meibomian glands and hair follicle/sebaceous glands by immunofluorescence tomography. J Invest Dermatol 135: 1175-1177, 2015.
Chai D, Ngai P, Jester BE, Reid KM, Juhasz T, Jester JV, Minckler DS, Brown DJ: Indentation testing of the optic nerve head and posterior sclera. Biomed Engineering Res 3: 18-27, 2014.
Winkler M, Simon M, Vu T, Gartner TL, Brown DJ, Lee A, Jester JV: A microfabricated, optically accessible device to study the effects of mechanical cues on collagen fiber organization. Biomedical Microdevices 16:59-67, 2014.
Suhalim JL, Parfitt GJ, Xie Y, De Pavia C, Pflugfelder SC, Shah T, Potma EO, Brown DJ, Jester JV. Effect of desiccating stress on meibomian gland function. The Ocular Surface 12: 59-68, 2014
Parfitt GJ, Xie Y, Geyfman M, Brown DJ, Jester JV: Absence of ductal hyper-keratinization in mouse age-related meibomian gland dysfunction (ARMGD). Aging 11:825-834, 2013.
Winkler M, Shoa G, Xie Y, Petsche SJ, Pinsky PM, Juhasz T, Brown D, Jester JV: Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma. Investigative Ophthalmology and Visual Science 54: 7293-72301, 2013.
Chai D, Juhasz T, Brown DJ, Jester JV: Non-linear optical (NLO) collagen cross-linking and mechanical stiffening: A possible photodynamic therapeutic approach to treating corneal ectasia. Journal of Biomedical Optics 18:038003, 2013
Age-Related Meibomian Gland Dysfunction, funded by the National Eye Institute.
Association for Research in Vision and Ophthalmology
International Society for Eye Research
American Society for Cell Biology
Experimental Pathology (PTH)