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

催乳素诱导蛋白对角膜伤口愈合和纤维化的影响

• 批准号: 10747116
• 负责人: Dimitrios Karamichos
• 金额: $ 47.74万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747116
• 关键词: Acceleration; Affect; Apoptosis; Biological; Biological Markers; Blinded; Blindness; Blood; Cancerous breast; Cells; Cementation; Cicatrix; Clinic; Clinical; Collagen Type III; Cornea; Corneal Diseases; Corneal Injury; Corneal Stroma; Data; Debridement; Deposition; Development; Disease; Drug Kinetics; Epidemiology; Epithelium; Exposure to; Extracellular Matrix; Eyedrops; Fibronectins; Fibrosis; Foundations; Future; Goals; Health; Human; In Vitro; Infection; Inflammation; Injections; Injury; Integrin alpha6; Integrin beta4; Investigation; Keratoconus; Keratoplasty; Link; Liquid substance; Maintenance; Mammary Gland Parenchyma; Measures; Metabolism; Miniature Swine; Mitochondria; Modeling; Molecular; Monkeys; Mus; Myofibroblast; Names; Operative Surgical Procedures; Patients; Persons; Pharmaceutical Preparations; Primates; Process; Prolactin; Proliferating; Protein Isoforms; Proteins; Public Health; Publishing; Quality of life; Reporting; Role; Saliva; Seminal fluid; Shapes; Signal Transduction; Signaling Protein; Stromal Cells; Techniques; Therapeutic Agents; Therapeutic Intervention; Thick; Thrombospondin 1; Time; Transforming Growth Factor beta; Trauma; United States Food and Drug Administration; Vision; corneal epithelial wound healing; corneal scar; cost; diagnostic biomarker; disease diagnosis; drug development; effective therapy; efficacy evaluation; improved; in vitro Model; in vivo; malignant breast neoplasm; migration; novel; novel therapeutics; polypeptide; prevent; protein expression; side effect; therapeutic target; wound; wound healing

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.

抽象的 角膜疾病和受伤是失明的第三大最常见原因，影响了1000万人 全世界。大多数角膜失明是由于疤痕而永久的。因此，控制进程 疤痕状态对于维持视力至关重要。手术技术正在改善；但是，他们 非常侵入性，可能会有长期的并发症。显然，需要进行治疗干预 为了减少角膜移植的需求，这是治疗最常用的技术 角膜疤痕。在当前的建议中，我们建议研究角膜疤痕治疗的新目标 称为催乳素诱导的蛋白（PIP）。 PIP是一个17 kDa的单多肽链，在 癌性乳房组织被认为是组织病理学诊断的诊断生物标志物 疾病。我们是第一个报告PIP在角膜背景下的作用的人。最初，我们显示了相互作用 在PIP和转化生长因子-β（TGF-β）之间，其调节所有TGF-β同工型的能力（在 体外研究），最近我们将PIP巩固为圆锥角膜的生物标志物（临床人类研究）。 在我们最近发表和初步的研究中，我们在体外和IN都观察到PIP的抗纤维化能力 体内，发现暴露于PIP后的细胞代谢和线粒体健康的调节（在 （体外）。因此，我们假设PIP在受伤/创伤之后对角膜伤口愈合至关重要 纤维化的存在。在体内和体外和实体模型中使用Minipigs，我们建议 进一步探索这些引人入胜的发现并揭示PIP的信号传导机制，并确定 PIP眼滴的功效，这似乎可以防止体内角膜恐怖。成功完成拟议的 研究最终可能导致开发新的角膜创伤眼药。我们提出了两个 完成但独立的特定目的是检查以下问题：首先，PIP的信号是什么 级联和行动机制？其次，我们可以开发基于PIP的眼滴吗？ 角膜疤痕治疗的替代和非侵入性溶液？与公共卫生相关 - 角膜 疤痕是一个主要的临床问题，通常导致视力丧失或部分丧失。 开发有效的，无创的角膜疤痕药，可能会帮助我们更近一点 解决视力威胁过程。