Sex Hormones and Keratoconus

性激素和圆锥角膜

• 批准号: 9490094
• 负责人: Dimitrios Karamichos
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9490094
• 关键词: 3-Dimensional; Affect; Aging; Androgens; Animal Model; Anterior; Autoimmune Diseases; Automobile Driving; Biological; Blindness; Cells; Cicatrix; Clinical; Collaborations; Collagen; Computers; Cornea; Corneal Stroma; Corneal dystrophy; Data; Defect; Dehydroepiandrosterone Sulfate; Dependence; Development; Discipline of Nursing; Disease; Disease Progression; Endocrine; Ensure; Estrogens; Estrone; Etiology; Extracellular Matrix; Eye diseases; Female; Fibroblasts; Fibrosis; Foundations; Gender; General Population; Glucocorticoids; Goals; Gonadal Steroid Hormones; Graft Survival; Growth; Herpetic Keratitis; Hormonal; Hormone imbalance; Hormones; Human; In Vitro; Incidence; Infection; Interleukin-16; International; Keratoconus; Keratoplasty; Lead; Left; Life; Link; Liquid substance; Mechanics; Mediator of activation protein; Metabolism; Mitochondria; Modality; Modeling; Molecular; Ocular Pathology; Onset of illness; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathogenesis; Pathological Dilatation; Pathway interactions; Patients; Phenotype; Physiological; Positioning Attribute; Pregnancy; Puberty; Public Health; Publishing; Reading; Reporting; Research Priority; Role; Route; Saliva; Salivary; Sampling; Scientist; Severity of illness; Shapes; Signal Transduction; Stem Cell Factor; Stromal Cells; System; Testing; Therapeutic; Thick; Thinness; Transplantation; Vision; Visual; Visual impairment; Work; base; clinically relevant; crosslink; cytokine; dehydroepiandrosterone; experience; eye dryness; in vitro Model; in vivo; in vivo Model; male; non-invasive system; novel; palliative; pregnant; prevent; success; targeted treatment; tool

PROJECT SUMMARY/ABSTRACT Keratoconus (KC) is the most common corneal dystrophy with clinical findings that include discomfort, visual disturbance, a negative impact on daily living (reading, driving, computer use and so on), and possible blindness if left untreated. KC affects approximately 1:400 people worldwide, including both males and females. During KC progression, the cornea slowly changes from its normal curved shape to a more conical shape, corneal thinning, and scarring, leading to vision distortion. Clinically, there are rather limited treatment options for KC patients, such as corneal transplantation and collagen cross-linking. Unfortunately, both corneal transplantation and collagen cross linking have their own limitations, primarily because the etiology of KC is largely unknown. As a result, we have yet to see the first animal model that mirrors KC dystrophy. As such, there is an urgent need to identify novel pathways and develop targeted treatment modalities. In 2012, we were the first to establish a novel in vitro 3-dimensional (3D) culture system consisting of human keratoconus cells (HKCs), which allows us to investigate and identify cellular mechanisms that are driving the disease. Since then, we have shown that our model can mirror the KC defects seen in vivo, including scarring, matrix thinning, and oxidative stress. Our preliminary data shows that sex hormones are a key KC mediator. Sex hormones were identically regulated both in vitro and in vivo based on results from three different systems: 3D in vitro model, human tears, and human saliva. Using these non-invasive systems we have begun unravelling an intriguing mechanism about KC onset and progression. We hypothesize that sex hormones imbalance initiate a cascade of downstream signals that collectively are responsible for the onset of KC. Naturally, we would like to pursue these findings and determine the role of sex hormones in KC. Excitingly, we are in a unique position where we can determine their role in vivo using human tears and saliva samples from KC and Healthy donors. We can then link our in vitro and in vivo findings and determine the mechanism of KC onset. In order to strengthen our proposal and ensure feasibility, we have put together a team of national and international experts in KC, both clinicians and basic scientists. We also have the support and collaboration of the National Keratoconus Foundation (NKCF). Successful completion of the proposed studies could ultimately lead to the development of novel treatments for KC. Relevance to Public Health – KC is a major clinical problem resulting in visual impairment worldwide. The lack of animal models require for us to develop novel, noninvasive tools for the treatment of KC. Ultimately, noninvasive therapeutics may lead to early arrest of the KC development. The proposed work is 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 (KC) 是最常见的角膜营养不良，临床表现包括不适、视力下降 干扰、对日常生活（阅读、驾驶、电脑使用等）的负面影响，以及可能的 如果不及时治疗，KC 会影响全世界大约 1:400 人，其中包括男性和女性。 在 KC 进展过程中，女性的角膜慢慢从正常的弯曲形状变为圆锥形。 形状、角膜变薄和疤痕，导致视力扭曲，临床上的治疗方法相当有限。 KC 患者的选择包括角膜移植和胶原交联，不幸的是，这两种方法都适用于角膜。 移植和胶原交联都有其自身的局限性，主要是因为 KC 的病因是 因此，我们还没有看到第一个反映 KC 营养不良的动物模型。 2012 年，我们迫切需要确定新的途径并开发有针对性的治疗方式。 率先建立了由人圆锥角膜组成的新型体外3维（3D）培养系统 细胞（HKC），这使我们能够研究和识别导致疾病的细胞机制。 从那时起，我们已经证明我们的模型可以反映体内看到的 KC 缺陷，包括疤痕、基质 我们的初步数据表明，性激素是 KC 的关键介质。 根据三个不同系统的结果，激素在体外和体内受到相同的调节：3D 使用这些非侵入性系统，我们已经开始解开体外模型、人类眼泪和人类唾液的谜团。 我们发现了有关 KC 发生和进展的有趣机制。 启动一系列下游信号，这些信号共同导致 KC 的发生。 想要研究这些发现并确定性激素在 KC 中的作用。令人兴奋的是，我们正处于一个阶段。 独特的位置，我们可以使用来自 KC 和的人类眼泪和唾液样本来确定它们在体内的作用 然后，我们可以将健康的捐赠者的体外和体内研究结果联系起来，并确定 KC 的发病机制。 为了加强我们的建议并确保可行性，我们组建了一个由国家和地区专家组成的团队 KC 的国际专家，包括出色的科学家和基础科学家，我们也得到了以下人士的支持和合作。 国家圆锥角膜基金会（NKCF）最终可以成功完成拟议的研究。 导致 KC 新型治疗方法的开发。 与公共卫生的相关性——KC 是导致全世界视力障碍的一个主要临床问题。 动物模型的发展需要我们开发新颖的、非侵入性的工具来治疗 KC。 非侵入性治疗可能会导致 KC 发展的早期停滞。拟议的工作是转化性的， 临床相关，并符合 NEI 的目标和研究重点，以了解 KC 并开发新的 减轻全球疾病负担的治疗方案。