Targeting Sex Hormone Receptors for Treatment of Meibomian Gland Dysfunction

University Of Missouri-Columbia, Columbia MO

Investigators

Abstract

Project Summary/Abstract The tear film on the ocular surface provides a protective barrier and serves as physiological lubricant to the ocular surface for ocular comfort and visual clarity. A lipid layer produced by the Meibomian glands (MGs) in the inner surface of eyelids constitutes the outermost layer of the tear film, with its function to prevent the evaporation of aqueous tear secreted by the lacrimal glands. Meibomian gland dysfunction (MGD) is the most prevalent cause of dry eye disease (DED) in the world with significant socioeconomic impact and public health concerns. To date, treatments for MGD or DED are mostly palliative for temporary symptom relief without targeting to improve MG function and abnormal evaporative loss of tears. It is well recognized that older age and female sex are the two significant risk factors for developing MGD and DED, although the prevalence varies widely among different age groups and sexes. For years, sex hormones have been postulated to play an important role in the maintenance of a normal tear film and ocular surface health. Like the related sebaceous glands (SG) of the skin, androgens are known to increase lipid synthesis and enhance the MG function. In contrast, a higher serum estrogen level was a significant predictor of worsening MG function in women. However, this consensus is unable to explain the higher prevalence of DED in postmenopausal women whose estrogen levels are reduced. In our preliminary study using estrogen receptor (ER) knockout (KO) mice, we found that loss of ER isoform α (ERα), but not ERβ, markedly increased the androgen receptor (AR) in the acinar cell nuclei of the meibomian glands in female KO mice. This finding suggests a crosstalk regulation at the hormonal receptor levels, i.e. ERα has an antagonistic effect on AR nuclear translocation in female MGs. In this application, we propose a new therapeutic target for MGD treatment by increasing the lipogenic function of AR via ER suppression. Up to date, a battery of pharmacological ER inhibitors has been widely used to block ER activity in ER+ breast and other cancers with satisfactory efficacy and clinical safety profiles. We will explore the therapeutic implications of two popular ER inhibitors, tamoxifen (a selective ER modulators or SERM) and fulvestrant (a selective ER downregulator or SERD) for better management and treatment of MGD. In Aim 1, ER inhibitors will be administrated systematically to suppress ER-related activity in wild type (WT) mice, a condition resemblance of ERα deletion in KO mice. It’s expected that treatment by ER inhibitors will augment AR activity and increase lipogenesis in the MGs of female mice. In Aim 2, a combined treatment of androgen and ER-inhibition is proposed to evaluate whether elevation of both androgen and AR can circumvent age-associated hormonal decline and maintain or restore MG function in aged mice. The outcomes from this proposal will establish a brand new therapeutic paradigm in targeting the regulation of sex hormones and their receptors for MGD and pave the avenue for a potential investigational new drug (IND) application of using currently available ER inhibitors for age-related MGD in postmenopausal women.