The role of extracellular vesicles in keratoconus pathogenesis

细胞外囊泡在圆锥角膜发病机制中的作用

• 批准号: 10595121
• 负责人: Dimitrios Karamichos
• 金额: $ 22.2万
• 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: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595121
• 关键词: Affect; Affinity; Age; Astigmatism; Bilateral; Biogenesis; Biologic Characteristic; Biological; Biological Markers; Biology; Biomechanics; Blood; Body Fluids; Categories; Cell Communication; Cell secretion; Cells; Chronic; Clinical; Clinical Research; Collection; Communication; Complex; Cornea; Corneal Diseases; Corneal Stroma; Corneal dystrophy; Country; DNA; Data; Data Analyses; Diabetes Mellitus; Diagnosis; Disease; Early Diagnosis; Endosomes; Environmental Risk Factor; Equipment; Event; Extracellular Space; Eye diseases; Female; Fingerprint; Future; Gender; Genetic; Goals; Hormonal; Human; Investigation; Keratoconus; Keratoplasty; Link; Lipid Bilayers; Lipid Binding; Lipids; Liquid substance; Malignant Neoplasms; Mediating; Mediator; Messenger RNA; Metabolic; MicroRNAs; Modality; Molecular; Monitor; Morphology; Nucleic Acids; Organ; Pathogenesis; Pathological Dilatation; Patients; Persons; Phenotype; Physiological Processes; Plasma; Postoperative Complications; Prognosis; Proteins; Proteomics; Public Health; Reporting; Research Priority; Resources; Risk; Role; Saliva; Serum; Severities; Severity of illness; Shapes; Signal Transduction; Site; Sjogren' s Syndrome; Source; Testing; Therapeutic; Thinness; Time; Tissues; Translating; Untranslated RNA; Urine; Vesicle; Vision; Visual impairment; Work; candidate marker; cell type; clinically relevant; cohort; corneal epithelial wound healing; early detection biomarkers; exosome; extracellular vesicles; eye dryness; innovation; insight; male; microRNA biomarkers; multidisciplinary; nervous system disorder; novel; novel diagnostics; novel marker; novel strategies; particle; protein biomarkers; recruit; sample collection; screening; sex; standard care; tool

PROJECT SUMMARY/ABSTRACT Keratoconus is a chronic, lifelong corneal dystrophy and affects approximately 1:400 people worldwide, including both males and females. Treating patients with advanced keratoconus has always been a challenge. Corneal transplantation remains the gold standard for treatment, however, significant risk of postoperative complications exist. Presently, keratoconus is diagnosed with specialized equipment and tests such as slit-lamp and Pentacam®. Early diagnosis, where irregular astigmatism can complicate things, is critical for the management of keratoconus. To-date, there are no biomarker tests which has consequently driven demand for novel approaches to assist in the diagnosis, management and/or treatment of keratoconus. Extracellular vesicles (EVs) are lipid bilayer-delimited particles released by cells, which may provide a real-time snapshot of the entire cell/tissue/organ in a non-invasive way. EVs can regulate physiological processes and contain components including proteins, miRNAs, DNA fragments, non-coding RNAs and lipids. Therefore, EVs hold promise for the discovery of future biomarkers. In the context of corneal diseases/dystrophies, tear fluid and tear EVs (tEVs) are the best candidate for biomarker investigations. Surprisingly, very few studies have been reported (only Dry eye and Sjogren’s syndrome) investigating tEVs. Our preliminary data provides strong evidence for the existence of tEVs in keratoconus patients that are phenotypically different from their healthy counterparts. The proposed clinical studies aim to unravel the role of tEVs in keratoconus pathobiology and discover relevant biomarkers associated with age, sex, and disease severity. During our preliminary studies, we have recruited a small cohort of healthy and keratoconus patients, and have put together a strong group of clinicians/collection sites that will assist us with sample collection during the proposed period. Our data suggests significant phenotypic differences in the tEVs derived from keratoconus patients, compared to healthy controls. We, therefore, propose an integrated multi-faceted “fingerprint” approach that will include tEV physical characterization, proteomics, and miRNA profiling. We believe that our strategy can shed light on future directions in this field for keratoconus diagnosis, management, and even treatment. Relevance to Public Health – KC is a major clinical problem resulting in visual impairment worldwide. The long- term implications of our study are important for KC patients since it could establish novel treatment modalities. Ultimately, the ability to effectively, and safely, manage/treat all KC patients, is vital. The proposed work is novel, translational, clinically relevant, and in line with NEI’s goals and research priorities to understand KC and develop novel treatment options to reduce the burden of the disorder worldwide.

项目摘要/摘要 角膜可乐是一种慢性，终生的角膜营养不良，影响了全球约1：400人， 包括男性和女性。治疗晚期角膜结构的患者一直是一个挑战。 角膜移植仍然是治疗的黄金标准，但是，术后的重大风险 并发症存在。目前，圆锥角膜被诊断为专门设备和测试，例如缝隙灯。 和Pentacam®。不规则散光会使事情变得复杂的早期诊断，对 圆锥角膜的管理。迄今为止，没有生物标志物测试，因此对 有助于诊断，管理和/或治疗角膜结构的新方法。 细胞外蔬菜（EV）是细胞释放的脂质双层二重压颗粒，这可能提供 整个细胞/组织/器官的实时快照以非侵入性的方式。电动汽车可以调节生理 过程并包含包括蛋白质，miRNA，DNA片段，非编码RNA和脂质的组件。 因此，电动汽车对发现未来的生物标志物保持了希望。在角膜的背景下 疾病/营养不良，泪液和泪水电动汽车（TEV）是生物标志物研究的最佳候选者。 令人惊讶的是，很少有研究（只有干眼症和Sjogren综合征）研究TEV。 我们的初步数据为圆锥角膜患者存在TEV的存在提供了有力的证据 在表型上与健康对应物不同。拟议的临床研究旨在揭示 圆锥角膜病理学中的TEV并发现与年龄，性别和疾病相关的相关生物标志物 严重程度。在我们的初步研究中，我们招募了一小部分健康和圆锥角膜患者， 并组建了一组强大的临床医生/收集网站，这些网站将在 拟议时期。我们的数据表明，源自圆锥角膜的TEV存在显着的表型差异 与健康对照相比，患者。因此，我们提出了一种集成的多面“指纹”方法 这将包括TEV物理表征，蛋白质组学和miRNA分析。我们相信我们的策略可以 阐明了该领域的未来方向，用于圆锥角膜诊断，管理甚至治疗。 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。长期 我们研究的术语含义对KC患者很重要，因为它可以建立新的治疗方式。 最终，有效，安全地管理/治疗所有KC患者的能力至关重要。拟议的工作是新颖的， 翻译，临床相关，并符合NEI的目标和研究重点，以了解KC并发展 减少全球疾病燃烧的新型治疗选择。