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.

项目概要/摘要 圆锥角膜是一种慢性、终生角膜营养不良，影响全球约 1:400 人， 包括男性和女性。治疗晚期圆锥角膜患者一直是一个挑战。 角膜移植仍然是治疗的金标准，但是术后风险很大 存在并发症。目前，圆锥角膜是通过专用设备和测试（例如裂隙灯）来诊断的 和 Pentacam®。早期诊断对于不规则散光的治疗至关重要。 圆锥角膜的管理。迄今为止，还没有生物标志物测试因此推动了对 协助诊断、管理和/或治疗圆锥角膜的新方法。 细胞外囊泡 (EV) 是细胞释放的脂质双层界定的颗粒，可提供 以非侵入方式对整个细胞/组织/器官进行实时快照。 EVs可以调节生理 加工并含有蛋白质、miRNA、DNA 片段、非编码 RNA 和脂质等成分。 因此，电动汽车有望发现未来的生物标志物。在角膜的背景下 疾病/营养不良、泪液和泪液 EV (tEV) 是生物标志物研究的最佳候选者。 令人惊讶的是，很少有研究报道（仅针对干眼症和干燥综合征）调查 tEV。 我们的初步数据为圆锥角膜患者中存在 tEV 提供了强有力的证据 其表型与健康同类不同。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，我们招募了一小群健康圆锥角膜患者， 并组建了一支强大的临床医生团队/收集站点，将在期间协助我们收集样本 建议的期限。我们的数据表明圆锥角膜衍生的 tEV 存在显着的表型差异 患者与健康对照者相比。因此，我们提出了一种集成的多方面“指纹”方法 其中包括 teV 物理表征、蛋白质组学和 miRNA 分析。我们相信我们的战略能够 阐明了圆锥角膜诊断、管理甚至治疗这一领域的未来方向。 与公共健康的相关性——KC 是导致全世界视力障碍的一个主要临床问题。长- 我们的研究的长期意义对于 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。拟议的工作新颖， 转化、临床相关，并符合 NEI 的目标和研究重点，以了解 KC 并开发 减轻全球疾病负担的新治疗方案。