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.

摘要 角膜疾病和损伤是第三大最常见的致盲原因，影响超过1000万人 国际吧大多数角膜失明是永久性的，由于疤痕;因此，控制进展， 而疤痕的状态对维持视力至关重要。手术技术正在改进;然而， 非常具有侵入性，并可能有长期并发症。显然，需要治疗性干预， 为了减少对角膜移植的需要，这是治疗角膜溃疡最常用的技术。 角膜疤痕在目前的建议中，我们建议研究一种新的角膜瘢痕治疗靶点 催乳素诱导蛋白（PIP）PIP是一条17-kDa的单链多肽链，在大肠杆菌中广泛表达。 癌性乳腺组织，并且被认为是用于这种组织病理学诊断的诊断生物标志物。 疾病我们是第一个报道PIP在角膜中的作用。最初，我们展示了 PIP与转化生长因子-β（TGF-β）之间的关系，以及其调节所有TGF-β亚型（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）。 在我们最近发表的和初步的研究中，我们观察了PIP在体外和体内的抗纤维化能力， 体内，并发现细胞代谢和线粒体健康的调制后，暴露于PIP（在 体外）。因此，我们假设PIP对于损伤/创伤后的角膜伤口愈合至关重要，而没有 存在纤维化。利用小型猪在体内和补充的体外和离体模型，我们建议 进一步探索这些令人信服的发现，并解开PIP的信号机制，以及确定 PIP滴眼液有效性，其似乎在体内防止角膜瘢痕形成。圆满完成拟议的 这些研究可能最终导致开发一种新的治疗角膜创伤的眼科药物。我们提出了两 补充，但独立的，具体的目的是检查以下问题：第一，什么是PIP的信号 级联和作用机制？第二，我们是否可以开发基于PIP的滴眼液， 角膜瘢痕治疗的替代和非侵入性解决方案？与公共卫生的相关性-角膜 瘢痕形成是一个主要的临床问题，并且常常导致视力的完全或部分丧失。的 开发一种有效的、非侵入性的角膜瘢痕形成药物，可能会帮助我们更进一步， 解决视力威胁的过程。