Functional and therapeutic roles of the Hedgehog signaling in meibomian glands development, renewal and dysfunction

Meibomian gland disease (MGD) is considered the leading cause of dry eye disease, a common multifactorial disease with a global prevalence of 5 to 50% and a major age-related disease of the ocular surface. Meibomian glands (MG) are modified sebaceous glands that line the margin of the eyelid, secrete lipids at the ocular surface, and participate in increasing the stability of the tear film. MGs are holocrine glands, which implies they are continually renewed since they deliver their secretory product, called meibum, by apoptosis. Thus, regulation of MG stem cells is crucial to ensure the proper function of MGs. With the aging process or disease condition, MGs can progressively lose their renewal capability and regress to an atrophic state. The pathogenesis of MGD and the mechanisms by which aging affects the renewal process remain largely unknown. Treatment options are currently limited mainly due to the lack of clear therapeutic targets and effective drug delivery strategies targeting the tissue of MGs. Thus, there is a critical need to understand signaling cascades underlying the renewal process of the MG that can be pharmacologically targeted to treat MGD. Our recent advances, with the aid of an NIH/NEI R21 (EY030661), have led us to discover a novel role of the primary cilium in MG development and maintenance suggesting a role of HH in the this process. The Hedgehog (HH) pathway plays a fundamental role in tissue development, homeostasis, and repair, including adult stem cell maintenance. To determine the therapeutic potential of targeting the HH pathway to treat MGD, we will investigate its role in MG development, maintenance, and renewal and trace the cell lineage of HH-responsive cells involved in MG homeostasis. We will target the HH pathway in mice using genetic and pharmacological HH modulators to improve age-related MGD. If successful, the outcome of this work will reveal mechanistic insights into MG renewal and define a novel paradigm for how to approach novel treatment strategies for MGD.