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 角膜疾病和损伤是导致失明的第三大常见原因，影响超过 1000 万人 在世界范围内，大多数角膜失明是由于疤痕造成的，因此控制其进展； 然而，疤痕状态对于维持视力至关重要。 具有很强的侵入性，并且可能会产生长期并发症，因此需要进行治疗干预。 以减少角膜移植的需要，这是最常用的治疗技术 在当前的提案中，我们建议研究角膜疤痕治疗的新靶点。 催乳素诱导蛋白 (PIP) 是一种 17 kDa 的单多肽链，广泛表达于体内。 癌性乳腺组织，被认为是组织病理学诊断的诊断生物标志物 我们是第一个报告 PIP 在角膜中的作用的人。 PIP 和转化生长因子-β (TGF-β) 之间的关系，以及它调节所有 TGF-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志物（临床人体研究）。 在我们最近发表的初步研究中，我们观察到 PIP 在体外和体内的抗纤维化能力 体内，并发现暴露于 PIP 后细胞代谢和线粒体健康的调节（在 因此，我们认为 PIP 对于损伤/外伤后角膜伤口愈合至关重要，而无需使用 PIP。 利用小型猪体内和互补的体外和离体模型，我们建议 进一步探索这些令人信服的发现，阐明 PIP 的信号传导机制，并确定 PIP滴眼液的功效，似乎在体内成功完成了预防角膜疤痕的工作。 研究最终可能导致开发一种治疗角膜创伤的新眼科药物。我们提出了两种建议。 互补但独立的具体目的是研究以下问题：首先，PIP 的信号传导是什么 其次，我们可以开发基于 PIP 的滴眼剂吗？ 角膜疤痕治疗的替代和非侵入性解决方案与公共健康的相关性 - 角膜 疤痕是一个主要的临床问题，通常会导致视力完全或部分丧失。 开发高效、非侵入性的角膜疤痕药物，可能会帮助我们更进一步 解决威胁视力的过程。