Utility of PIP as a Novel Keratoconus Biomarker

PIP 作为新型圆锥角膜生物标志物的实用性

• 批准号: 10018023
• 负责人: Dimitrios Karamichos
• 金额: $ 30.18万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018023
• 关键词: Address; Adolescence; Affect; Age; Agreement; Animal Model; Anterior uveitis; Automobile Driving; Basic Science; Biological; Biological Markers; Blindness; Blood; Blood specimen; Cells; Clinical; Clinical Research; Collagen; Computers; Cornea; Corneal Diseases; Corneal Stroma; Corneal dystrophy; Data; Denmark; Descemet' s membrane; Detection; Development; Diagnosis; Diffuse; Disease; Down-Regulation; Early Diagnosis; Early treatment; Ensure; Epithelial; Epithelium; Etiology; Eye Injuries; Female; Fibroblasts; Follow-Up Studies; Foundations; Fuchs' Endothelial Dystrophy; Future; Gender; Genes; Genetic; Genetic study; Glycoproteins; Goals; Human; In Situ; In Vitro; Individual; Keratoconus; Keratoplasty; Knowledge; Left; Life; Liquid substance; Longterm Follow-up; Modality; Myopia; Non-Insulin-Dependent Diabetes Mellitus; Norway; Open-Angle Glaucoma; Operative Surgical Procedures; Pathogenesis; Pathology; Patient Care; Patients; Play; Prevention; Prolactin; Proteins; Public Health; Publishing; Quality of life; Reading; Reporting; Research; Research Personnel; Role; Route; Saliva; Sampling; Serum; Severities; Shapes; Specificity; Systemic disease; Thinness; Time; Tissues; Uveitis; Vision; Visual; Visual impairment; Work; base; clinically relevant; cohort; corneal scar; crosslink; disability; in vivo; male; malignant breast neoplasm; novel; novel diagnostics; ocular surface; potential biomarker; programs; protein expression; rapid diagnosis; recruit; skin disorder; three dimensional cell culture; tool

PROJECT SUMMARY/ABSTRACT Keratoconus (KC) is the most common corneal dystrophy, with adverse corneal changes that can dramatically affect vision. During KC progression, the cornea can show several pathologies, including fragmentation of Bowman’s layer, thinning of stroma and overlying epithelium, folds or breaks in Descemet’s membrane, and variable amounts of diffuse corneal scarring. Clinically, limited treatment options for KC patients include corneal transplantation and collagen cross-linking. Unfortunately, both corneal transplantation and collagen cross-linking have their own limitations. To date, the etiology and pathogenesis of KC remains unclear. As such, there is an urgent need to identify viable biomarker(s) that can help with the early diagnosis and treatment of KC. In 2014, we were the first to report the role and significant modulation of prolactin-induced protein (PIP) in vitro (3D cultures with human KC cells) and in vivo (human tear samples), and question its role during KC development and progression. Our preliminary data shows that PIP is significantly downregulated in KC patients when compared to Healthy individuals. Interestingly, downregulation of PIP was seen in three different human biological fluids: saliva, tears, and blood (serum). Furthermore, our preliminary data shows that PIP is not modulated in other relevant diseases, such as Uveitis and Type II Diabetes, suggesting potential specificity to KC. Even more strikingly, new data shows that PIP expression levels returned to normal on KC patients that had received corneal transplants. We posit that PIP can serve as a biomarker for KC onset and progression drive the development of future non-invasive treatment modalities. The current proposal is focused solely on PIP, with three main goals: 1) Cement PIP as a KC biomarker, 2) Determine the power and specificity of PIP, and 3) Determine PIP expression following known KC treatments. To ensure that we achieve our goals, we have assembled a large cohort of experts in the field from multiple clinical and research centers, as well as from the National Keratoconus Foundation (NKCF). Successful completion of the studies proposed will be a breakthrough in KC research and will alter current standards of care for patients with KC. Relevance to Public Health – KC is a major clinical problem resulting in visual impairment worldwide. There is an urgent need to develop novel diagnostic tools for the detection and treatment of KC in the early stages. Ultimately, the primary goal is to enable people with KC to live a normal life with little or no visual disability. The proposed work will move the field forward, is translational, clinically relevant, and in line with NEI’s program goals: “Apply the knowledge acquired from discoveries in the basic science of the cornea and other tissues of the ocular surface to the diagnosis, prevention, and treatment of ocular injury and disease”.

项目摘要/摘要 角膜核（KC）是最常见的角膜营养不良，不良角膜变化可以极大地变化 影响视力。在KC进展过程中，角膜可以显示几种病理，包括 鲍曼（Bowman 可变量的弥漫性角膜疤痕。临床上，KC患者的有限治疗选择包括 角膜移植和胶原蛋白交联。不幸的是，角膜移植和胶原蛋白 交联有自己的局限性。迄今为止，KC的病因和发病机理尚不清楚。作为 这样，迫切需要确定可以帮助早期诊断和 KC的处理。 2014年，我们是第一个报告催乳素引起的作用和显着调节的人 蛋白质（PIP）体外（具有人类KC细胞的3D培养物）和体内（人撕裂样品），并质疑其作用 在KC开发和进展过程中。我们的初步数据表明，PIP在 与健康个体相比，KC患者。有趣的是，在三个中看到了PIP的下调 不同的人类生物液：唾液，眼泪和血液（血清）。此外，我们的初步数据表明 在其他相关疾病（例如葡萄膜炎和II型糖尿病）中，PIP没有调节，这表明潜力 KC的特异性。更令人惊讶的是，新数据表明，PIP表达水平在KC上恢复正常 接受了角膜移植的患者。我们肯定PIP可以用作KC发作的生物标志物 和进展推动了未来非侵入性治疗方式的发展。电流 提案仅集中在PIP上，具有三个主要目标：1）水泥PIP作为KC生物标志物，2）确定 PIP的功率和特异性，以及3）确定已知KC处理后的PIP表达。确保这一点 我们实现了目标，我们从多个临床和 研究中心以及国家圆锥角膜基金会（NKCF）。成功完成 提出的研究将是KC研究的突破，并将改变目前的护理标准 KC。 与公共卫生有关 - KC是一个主要的临床问题，导致全球视觉障碍。有 迫切需要开发新颖的诊断工具，以在早期阶段检测和治疗KC。 最终，主要目标是使KC患者能够过着几乎没有视觉障碍或没有视觉障碍的正常生活。这 拟议的工作将向前进，翻译，临床相关，并符合NEI的计划 目标：“应用从角膜基础科学和其他时间的发现中获得的知识 眼科诊断，预防和治疗眼损伤和疾病的表面”。