Modifying the extracellular matrix to prevent dry eye disease and age-related Meibomian gland dysfunction (ARMGD)

Project summary The prevalence of dry eye disease (DED) ranges from ~5 to 50% of the general population with an estimated US$ 3.8 billion dollars in associated medical costs. Symptoms of DED include pain, fatigued and/or sore eyes, photophobia and blurred vision, which lead to a decrease in productivity and reduce the quality of life. Unfortunately, treatment options for DED are limited. Clinical studies suggest 85% of overall DED cases are caused by Meibomian gland dysfunction (MGD). As humans and mice age, their Meibomian glands (MGs) undergo age-related changes, including decreased acinar basal cell proliferation and atrophy, and these changes result in age related-MGD (ARMGD). The precise cause of ARMGD remains elusive, which makes the development of therapies extremely challenging. Hyaluronan (HA) is a major extracellular component that interacts and binds to a myriad of molecules forming complex macromolecules which regulate major physiological functions, such as development and stem cell specification. Our recently published work shows that compound HA synthase (Has)-1 and -3 null mice, namely Has1-/-;Has3-/- mice, have enlarged MGs when compared to age matched wild-type (wt) mice. Our preliminary data show that the MGs of Has1-/-;Has3-/- mice continue to increase in size throughout life, and, interestingly, these mice do not develop ARMGD. At 1 year of age, Has1-/-;Has3-/- mice have a striking 4-fold increase in MG volume and an overall 10-fold increase in lipid production, compared to age matched wt mice. We hypothesize that the increase in HA expression in and around the MGs of Has1-/-;Has3-/- mice is capable of maintaining viable progenitor cells as they age, which in turn prevents ARMGD. Specific aim 1 of this proposal will characterize the extracellular matrix in the MGs of wt and Has1-/-;Has3-/- mice with a focus on the composition of the HA matrix. Specific aim 2 of this proposal will analyze the distribution of MG progenitor and proliferating cells in order to identify how the MGs of Has1- /-;Has3-/- mice enlarge over time. This aim will also characterize the lipid composition of the meibum, and verify whether enlarged glands can prevent DED. Importantly, although Has1-/-;Has3-/- mice lack two isoforms of the enzyme responsible for HA biosynthesis, they up-regulate the third isoform (Has2), and, in turn, present a significant increase in HA expression in and around MGs when compared to wt mice. Therefore, we also hypothesize that increasing Has2 expression and HA bioavailability within MGs could prevent ARMGD in aged wt mice. Specific aim 3 will test whether Has2 overexpression and FDA approved HA-based treatment regimens to increase the bioavailability of HA within tarsal plates and MGs can prevent ARMGD in wt mice.