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

摘要 角膜疾病和损伤是导致失明的第三大常见原因，影响着1000多万人 全世界。由于疤痕形成，大多数角膜失明是永久性的；因此，控制进展 而疤痕的状态对视力的维持至关重要。手术技术正在改进；然而，他们 侵袭性很强，可能会有长期的并发症。显然，有必要进行治疗性干预 为了减少对角膜移植的需求，这是最常用的治疗技术 角膜上的疤痕。在目前的方案中，我们建议研究一种治疗角膜疤痕的新靶点。 被称为催乳素诱导蛋白(PIP)。PIP是一种17 kDa的单一多肽链，广泛表达于 乳腺癌组织，被认为是组织病理学诊断的诊断生物标志物。 疾病。我们首次报道了PIP在角膜中的作用。最初，我们展示了互动 在PIP和转化生长因子-β(转化生长因子-β)之间，以及它调节所有转化生长因子-β亚型的能力(在 体外研究)，最近我们将PIP作为圆锥角膜的生物标记物(临床人类研究)。 在我们最近发表的初步研究中，我们观察了PIP在体外和体外的抗纤维化能力。 体内，并发现暴露于PIP后细胞代谢和线粒体健康的调节(在 体外培养)。因此，我们假设PIP对于角膜创伤愈合是至关重要的，在损伤/创伤后，没有 有纤维化的存在。利用体内小型猪和互补的体外和体外模型，我们建议 进一步探索这些令人信服的发现，解开PIP的信号机制，并确定 PIP滴眼液的疗效，似乎可以预防体内的角膜瘢痕。圆满完成拟议中的 研究最终可能导致开发一种治疗角膜创伤的新眼药。我们建议两个 补充的，但独立的，具体的目的是检查以下问题：第一，PIP的信号是什么 级联和作用机制？其次，我们能否开发出基于PIP的眼药水，可以用作 角膜疤痕治疗的替代和非侵入性解决方案？与公共卫生相关--角膜 疤痕形成是一个主要的临床问题，通常会导致完全或部分失明。这个 开发高效、非侵入性的角膜疤痕药物，可能会帮助我们更接近 解决一个威胁视力的过程。

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.