Meibomian gland dysfunction (MGD) is believed to be the leading cause of dry eye disease, which affects the quality of life of millions of people in the US. MGD is characterized by terminal excretory duct obstruction, hyperkeratinization of the ductal epithelium, increased viscosity of meibum and meibomian gland atrophy/dropout. Currently the mechanism of MGD is not known. Risk factors include old age, androgen deficiency and exposure to 13-cis retinoic acid (RA). Given that RA causes prototypical MGD, I propose to study the mechanism of MGD using human meibomian gland cell cultures and mouse models exposed to RA. I hypothesize that RA inhibits meibomian gland cell proliferation and induces cell death by affecting specific intracellular pathways and upregulating specific death-inducing proteins. In addition, I hypothesize that RA promotes meibomian gland keratinization via specific keratinization-related proteins. To counteract RA-induced MGD, I propose to use two hormones, growth hormone (GH) and insulin-like growth factor-1 (IGF-1). GH/IGF-1 is well-known to promote cell proliferation and cell survival, and plays roles in the proliferation and differentiation of other types of sebaceous gland cells. I hypothesize that GH/IGF-1 signaling intersects the RA-induced signaling pathways and antagonizes the protein changes involved in proliferation, cell death and keratinization. To test my hypotheses, I will use a variety of experimental procedures, including human cell cultures, immunoassays, enzyme assays, qRT-PCR, RNA silencing, fluorescence microscopy, flow cytometry, mouse models, histology and hormone treatments.
My specific aims are to: 1) determine the mechanism by which 13-cis RA induces cell cycle arrest, cell death and keratinization in immortalized human meibomian gland epithelial cells;2) elucidate how GH/IGF-1 interrupts the generation of these 13-cis RA-induced cellular sequelae;3) examine the meibomian gland histology in mice with altered GH signaling;4) determine the effect of 13-cis RA on inducing MGD including gland atrophy and ductal hyperkeratinization in wild type (WT) mice;and 5) determine the effect of topical treatment with GH/IGF-1 on 13-cis RA induced MGD in WT mice. My long-term objective is to better understand the mechanism of MGD and to translate this information into a potential treatment for MGD.

Public Health Relevance

Meibomian gland dysfunction (MGD) is the primary cause of dry eye disease, which afflicts tens of millions of Americans. Currently the mechanism of MGD is not known and there is no effective treatment. I propose to study the underlying mechanism of MGD by using human cell culture and mouse models and develop a treatment of MGD by using growth hormone and insulin-like growth factor-1, two hormones that may have tremendous benefit for the meibomian gland.

National Institute of Health (NIH)
National Eye Institute (NEI)
Career Transition Award (K99)
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Special Emphasis Panel (ZEY1)
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Agarwal, Neeraj
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Schepens Eye Research Institute
United States
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