Meibogenesis in Health, Disease, and Aging - Administrative Supplement

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: 3R01EY027349-07S1
NIH Institute/Center: NIH
Principal Investigator: Igor Butovich