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: 10723125
• 负责人: Dimitrios Karamichos
• 金额: $ 4.8万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723125
• 关键词: Address; Adolescence; Affect; Age; Agreement; Animal Model; Anterior uveitis; Automobile Driving; Basic Science; Biological; Biological Markers; Blindness; Blood; Blood specimen; Body Fluids; Cells; Cementation; Clinical; 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; Epithelium; Etiology; Eye Injuries; Eye diseases; Female; Fibroblasts; Follow-Up Studies; Foundations; Fuchs' Endothelial Dystrophy; Future; Gender; Genes; Genetic; Genetic study; Glycoproteins; Goals; Human; Human body; In Situ; In Vitro; Individual; Keratoconus; Keratoplasty; Knowledge acquisition; 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; Persons; Play; Prevention; Productivity; 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; clinically relevant; cohort; corneal scar; crosslink; diagnostic tool; disability; in vivo; male; malignant breast neoplasm; novel; novel diagnostics; ocular surface; potential biomarker; programs; protein expression; rapid diagnosis; recruit; saliva sample; skin disorder; three dimensional cell culture

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”.

项目总结/摘要 圆锥角膜（KC）是最常见的角膜营养不良，其不良角膜变化可显著影响角膜的生长， 影响视力。在KC进展期间，角膜可以显示出几种病理，包括角膜的碎裂。 Bowman层，基质和上覆上皮变薄，后弹力膜折叠或断裂，以及 不同程度的弥漫性角膜瘢痕临床上，KC患者的有限治疗选择包括 角膜移植和胶原交联。不幸的是，角膜移植和胶原蛋白 交联有其自身的局限性。迄今为止，KC的病因和发病机制仍不清楚。作为 因此，迫切需要鉴定可以帮助早期诊断的可行的生物标志物， KC的治疗2014年，我们首次报道了催乳素诱导的 在体外（与人KC细胞的3D培养物）和体内（人泪液样品）中检测PIP蛋白，并质疑其作用 KC的发展和进步。我们的初步数据显示，PIP在 KC患者与健康人相比。有趣的是，PIP的下调在三个 不同的人体生物液体：唾液、眼泪和血液（血清）。此外，我们的初步数据显示， PIP在其他相关疾病如葡萄膜炎和II型糖尿病中不受调节，这表明PIP在治疗糖尿病中的潜在作用。 对KC的特异性。更引人注目的是，新的数据显示，PIP表达水平在KC上恢复正常， 接受角膜移植的患者。我们认为PIP可以作为KC发病的生物标志物 和进展推动了未来非侵入性治疗方式的发展。当前 该提案仅关注PIP，有三个主要目标：1）巩固PIP作为KC生物标志物，2）确定 PIP的功效和特异性，以及3）在已知KC处理后测定PIP表达。确保 我们实现了我们的目标，我们已经聚集了大量的专家在该领域从多个临床和 研究中心，以及国家圆锥角膜基金会（NKCF）。成功完成 拟议的研究将是KC研究的一个突破，并将改变目前对KC患者的护理标准。 KC. 与公共卫生的相关性- KC是导致世界范围内视力损害的主要临床问题。有 迫切需要开发新的诊断工具，用于在早期阶段检测和治疗KC。 最终，主要目标是使KC患者能够过上正常的生活，很少或没有视力残疾。的 建议的工作将推动该领域向前发展，是转化的，临床相关的，并符合NEI的计划 目标：“应用从角膜和其他组织的基础科学发现中获得的知识 眼表对眼损伤和疾病的诊断、预防和治疗的作用”。

项目成果

Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms.

• DOI: 10.3390/biom13040696
• 发表时间: 2023-04-20
• 期刊: Biomolecules
• 影响因子: 5.5

Salivary Exosomes in Health and Disease: Future Prospects in the Eye.

• DOI: 10.3390/ijms24076363
• 发表时间: 2023-03-28
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Liu, Angela;Hefley, Brenna;Escandon, Paulina;Nicholas, Sarah E.;Karamichos, Dimitrios
• 通讯作者: Karamichos, Dimitrios

Treatment of Non-Infectious Corneal Injury: Review of Diagnostic Agents, Therapeutic Medications, and Future Targets.

• DOI: 10.1007/s40265-021-01660-5
• 发表时间: 2022-03
• 期刊: Drugs
• 影响因子: 11.5
• 作者: Dang DH;Riaz KM;Karamichos D
• 通讯作者: Karamichos D