The Impact of Prolactin Induced Protein in Corneal Wound Healing and Fibrosis

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ABSTRACT Corneal disease and injury are the third most common causes of blindness, affecting over 10 million people worldwide. The majority of corneal blindness is permanent due to scarring; therefore, controlling the progression and state of scarring is crucial for the maintenance of vision. Surgical techniques are improving; however, they are very invasive and may have long-term complications. Clearly, there is a need for therapeutic intervention in order to reduce the need for corneal transplantation, which is the most commonly used technique for treating corneal scarring. In the current proposal, we propose to investigate a novel target for corneal scarring treatment known as Prolactin-Induced Protein (PIP). PIP is a 17-kDa single polypeptide chain that is widely expressed in cancerous breast tissue and is regarded as a diagnostic biomarker for the histopathological diagnosis of this disease. We were the first to report the role of PIP in the context of cornea. Initially, we showed the interplay between PIP and the transforming growth factor-β (TGF-β), and its ability to modulate all the TGF-β isoforms (in vitro studies), and more recently we cemented PIP as a biomarker for keratoconus (clinical human studies). During our recently published and preliminary studies, we observed PIP’s anti-fibrotic ability both in vitro and in vivo, and discovered modulation of cellular metabolism and mitochondria health following exposure to PIP (in vitro). Thus, we hypothesize that PIP is critical for corneal wound healing, following an injury/trauma, without the presence of fibrosis. Utilizing minipigs in vivo and complementary in vitro and ex vivo models, we propose to further explore these compelling findings and unravel the signaling mechanisms of PIP as well as determine the efficacy of PIP eye drops, which seem to prevent corneal scaring in vivo. Successful completion of the proposed studies could ultimately lead to the development of a new ocular drug for corneal trauma. We propose two complementary, but independent, specific aims to examine the following questions: First, what is PIP’s signaling cascade and mechanism-of-action? Second, can we develop PIP-based eye drops that can be used as an alternative and non-invasive solution for corneal scarring treatment? Relevance to Public Health – Corneal scarring is a major clinical problem and more often than not leads to complete or partial loss of vision. The development of efficient, non-invasive corneal scarring drug, will likely help us move a step closer towards resolving a sight threatening process.