Sex Hormones and Keratoconus

项目总结/摘要 圆锥角膜（KC）是最常见的角膜营养不良，其临床表现包括不适、视觉障碍、视力下降和视力下降。 干扰，对日常生活（阅读，驾驶，电脑使用等）产生负面影响，并可能 如果不治疗的话会失明。KC影响全球约1：400的人，包括男性和女性。 女性在KC进展期间，角膜从其正常弯曲形状缓慢地改变为更圆锥形的形状。 形状，角膜变薄和疤痕，导致视力失真。在临床上， KC患者的选择，如角膜移植和胶原交联。不幸的是，两个角膜 移植和胶原交联有其自身的局限性，主要是因为KC的病因是 大部分未知。因此，我们还没有看到第一个反映KC营养不良的动物模型。因此，在本发明中， 迫切需要确定新的途径和开发有针对性的治疗方式。2012年我们 是第一个建立了一种新的体外三维（3D）培养系统，包括人圆锥角膜 细胞（HKC），这使我们能够调查和识别驱动疾病的细胞机制。 从那时起，我们已经表明，我们的模型可以反映在体内看到的KC缺陷，包括疤痕，基质 变薄和氧化应激。我们的初步数据表明，性激素是一个关键的KC调解人。性 基于来自三种不同系统的结果，在体外和体内对激素进行了相同的调节：3D 体外模型、人眼泪和人唾液。利用这些非侵入性的系统， KC发病和进展的一个有趣机制。我们假设性激素失衡 启动一系列下游信号，共同负责KC的发作。我们自然 希望继续研究这些发现并确定性激素在KC中的作用。令人兴奋的是，我们在一个 独特的位置，我们可以使用KC的人类泪液和唾液样本确定其在体内的作用， 健康的捐赠者。然后，我们可以将我们的体外和体内研究结果联系起来，并确定KC发病的机制。在 为了加强我们的建议，并确保可行性，我们已经组建了一个国家和 KC的国际专家，包括临床医生和基础科学家。我们还得到了以下方面的支持和合作： 国家圆锥角膜基金会（NKCF）成功完成拟议的研究， 导致KC的新治疗方法的发展。 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。缺乏 动物模型的建立要求我们开发新的、非侵入性的工具来治疗KC。最后， 非侵入性治疗可能导致KC发展的早期停滞。拟议的工作是翻译， 临床相关，并符合NEI的目标和研究重点，以了解KC和开发新的 治疗选择，以减少世界范围内的疾病负担。

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.