Meibogenesis in Health, Disease, and Aging

PROJECT SUMMARY: The goal of our project is to investigate the molecular mechanisms of induction and
decline of meibogenesis in Meibomian glands (MG) embedded in tarsal plates of humans and mice.
Meibogenesis is defined as an intricate array of catabolic and anabolic reactions, and corresponding regulatory
and signaling mechanisms, that lead to formation of a holocrine secretion called meibum. Meibum is a unique
lipid secretion that is comprised primarily of extremely long chain and branched wax esters, cholesteryl esters,
and a range of other, more complex, compounds. Meibum is vital to the ocular health as it forms a protective
layer that isolates the surface of the eye from the environment, and improves vision by changing the refractive
properties of the cornea. Lipid composition of meibum is very conservative in normal conditions, implying that
lipid homeostasis of MG is typically under tight control of yet to be identified regulatory mechanisms. However,
a MG pathology called MG dysfunction (MGD) results in a decline in meibum production, or adverse changes
in its composition, or both, negatively affecting the ocular surface physiology, vision, and quality of life in
general. MGD is a major contributing factor to a widespread condition called Dry Eye syndrome (DES). MGD
and DES affect up to 40% of the general population worldwide, disproportionately affecting elderly. Earlier, we
demonstrated that mice are credible models of human MG for studying meibogenesis. Using various lines of
mutant mice, we have established major genes and enzymes that are involved in meibogenesis. However, the
mechanisms of its initiation and regulation remain unknown. Previous attempts to induce meibogenesis in cell
cultures (such as immortalized human MG epithelial cells) failed, as no meibomian lipids have been produced
in any tested conditions. Thus, our aim is to elucidate the mechanism of meibogenesis induction and decline in
vivo by conducting transcriptomic, lipidomic, immunohistochemical, and physiological characterization of
developing and aging MG, using mice that undergo prenatal and postnatal development and aging as primary
animal model, and human subjects of different ages. These experiments should allow us to determine a
timeline of changes in developing, maturing, and aging MG, and correlate MG transcriptome in general, and
key genes of meibogenesis specifically, with the expression levels of specific enzymes and their corresponding
lipid products. Special consideration will be given to genes that simultaneously: 1) are highly expressed in MG,
2) encode signaling factors that are already known to control tissue growth, cell differentiation and lipid
homeostasis in MG and/or other tissues, and 3) whose expression levels undergo significant changes in
developing and aging MG. These results will provide critically important information for future in-depth studies
of MG physiology in the norm and pathology.

Grant Number: 5R01EY027349-07
NIH Institute/Center: NIH
Principal Investigator: Igor Butovich