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 圆锥角膜(KC)是最常见的角膜营养不良，伴有严重的角膜病变。 影响视力。在KC进展过程中，角膜可以表现出几种病理变化，包括角膜碎裂 鲍曼氏层，间质和覆盖的上皮变薄，Descemet膜折叠或断裂，以及 不同程度的角膜弥漫性疤痕。临床上，对KC患者的有限治疗选择包括 角膜移植和胶原交联剂。不幸的是，角膜移植和胶原蛋白 交联剂有其自身的局限性。到目前为止，KC的病因和发病机制尚不清楚。AS 因此，迫切需要寻找活的生物标志物(S)，以帮助早期诊断和治疗 KC的治疗。2014年，我们首次报道了催乳素诱导的作用和显著调节 蛋白质(PIP)在体外(与人KC细胞3D培养)和体内(人泪液样本)的表达，并质疑其作用 在KC的发展和进步过程中。我们的初步数据显示，PIP在 将KC患者与健康人进行比较。有趣的是，PIP的下调出现了三次 不同的人体体液：唾液、泪水和血液(血清)。此外，我们的初步数据显示， PIP在其他相关疾病中没有调节，如葡萄膜炎和II型糖尿病，这表明 对KC的特异性。更引人注目的是，新数据显示KC的PIP表达水平恢复到正常水平 接受过角膜移植的患者。我们推测PIP可作为KC发病的生物标志物 和进步推动了未来非侵入性治疗模式的发展。海流 提案只关注PIP，有三个主要目标：1)将PIP作为KC生物标记物；2)确定 PIP的能力和特异性，以及3)在已知的KC治疗后决定PIP的表达。以确保 我们实现了我们的目标，我们汇集了一大批该领域的专家，他们来自多个临床和 研究中心，以及国家圆锥角膜基金会(NKCF)。圆满完成 拟议的研究将是KC研究的一个突破，并将改变目前对患有糖尿病患者的护理标准 KC。 与公共健康相关-KC是导致全球范围内视力障碍的主要临床问题。的确有 迫切需要开发新的诊断工具，以便在早期阶段发现和治疗KC。 归根结底，主要目标是使KC患者能够过上正常的生活，几乎没有视力残疾。这个 拟议的工作将推动该领域的发展，具有翻译性、临床相关性，并与NEI的计划保持一致 目标：将从发现中获得的知识应用于角膜和其他组织的基础科学中 眼表对于诊断、预防和治疗眼部损伤和疾病具有重要意义。