The Intimate Interplay Between Keratoconus, Sex Hormones, and the Anterior Pituitary

项目摘要/摘要 圆锥角膜(KC)是一种进行性、非炎症性扩张性角膜病变，以变陡为特征。 角膜变薄，散光不规则，近视和疤痕形成。尽管引入了角膜 为了阻止进展和改进巩膜接触镜设计，角膜移植仍然存在 治疗肯塔基州的圣杯。KC是目前导致角膜移植的最常见的适应症之一。 此外，现在有越来越多的证据表明，即使在角膜移植后，KC也会复发。迄今为止， KC的病因和发病机制尚不清楚，包括复发的原因。因此，有一个 迫切需要了解和定义KC的发病/进展。我们的团队正在带头进行KC研究 性激素和促性腺激素，这将为这个在很大程度上被忽视的话题提供宝贵的贡献 尽管有临床观察和发现。我们小组报道了一种新的性激素调节的KC生物标志物， 催乳素诱导蛋白(PIP)，发现促性腺激素及其受体在KC中存在。它是 因此，公平地问：“促性腺激素在人类角膜和KC中的作用是什么？”和“有没有一个功能性的 这些促性腺激素及其受体在解释KC病理生物学中的作用？“我们的初步数据显示 许多人认为是所有激素之王的促性腺激素释放激素(GnRH)在 KCS与健康对照组比较。促性腺激素释放激素受体(GnRH-R)存在于KC基质细胞中，并受 通过黄体生成素(L H)促性腺激素。促黄体生成素和卵泡刺激素(FSH)依次受 性腺和肾上腺性激素(脱氢表雄酮-脱氢表雄酮、雌酮和雌三醇) 美国将在肯塔基州保持不平衡。这些同性荷尔蒙是在角膜之后系统地调节的 交联剂。总而言之，我们的数据表明，KC高度依赖于 促性腺激素和性激素。具体地说，我们假设激素分泌异常是 与促卵泡激素和促黄体生成素有关，随后是性激素失调，最终影响角膜 介导KC发生发展的微环境。目前的提案旨在使调查结果 在体外、体外和体内进行验证，以最大限度地提高可译性。以确保我们实现我们的目标 为了实现这些目标，我们从多个中心召集了一大批该领域的专家。成功完成 拟议的研究将是一个突破，改变了目前对KC患者的护理标准。 与公共健康相关-KC是导致全球范围内视力障碍的主要临床问题。的确有 迫切需要描述KC的病理生物学，并开发新的检测和治疗工具。 最终，目标是使KC患者能够过上正常的生活，几乎没有或没有视力残疾。建议数 这项工作是翻译性的，与临床相关，并与NEI的计划目标一致：“应用所获得的知识 从角膜和眼表其他组织的基础科学发现到诊断， 预防和治疗眼部损伤和疾病“。

PROJECT SUMMARY/ABSTRACT Keratoconus (KC) is a progressive, non-inflammatory ectatic corneal disorder that is characterized by steepening and thinning of the cornea, irregular astigmatism, myopia, and scarring. Despite the introduction of corneal crosslinking to stop progression and improvements in scleral contact lens designs, corneal transplants remain the holy grail of treating KC. KC is currently one of the most common indications leading to corneal transplants. Furthermore, there is now increasing evidence that KC recurs even following corneal transplantation. To-date, the KC etiology and pathogenesis remains unclear, including the reasons for recurrence. As such, there is an urgent need to understand and define the onset/progression of KC. Our group is spearheading KC research on sex hormones and gonadotropins, which will provide valuable contributions to a topic that is largely ignored despite clinical observations and findings. Our group reported a novel sex hormone-regulated KC biomarker, prolactin-induced protein (PIP), and discovered the existence of gonadotropins and their receptors in KC. It is therefore fair to ask, “what is the role of gonadotropins in the human cornea and KC?” and “Is there a functional role of these gonadotropins and their receptors that can explain KC pathobiology?”. Our preliminary data shows dysregulation of what many consider the “king of all hormones”, Gonadotropin-releasing hormone (GnRH), in KCs when compared to healthy controls. GnRH receptor (GnRH-R) is found in KC stromal cells and is modulated by luteinizing hormone (LH) gonadotropin. LH and follicle-stimulating hormone (FSH), in turn, are modulated by gonadal and adrenal sex hormones (Dehydroepiandrosterone-DHEA, Estrone, and Estriol) previously shown by us to be imbalanced in KCs. These same sex hormones are modulated, systemically, following corneal crosslinking. Together, our data suggests that KC is highly dependent on the balance and interactions of gonadotrophins and sex hormones. Specifically, we hypothesize that hormonal secretion abnormalities are associated with FSH and LH, followed by sex hormone dysregulation that ultimately affects the corneal microenvironment mediating KC onset and progression. The current proposal is designed so that findings are validated both in vitro, ex vivo and in vivo, in order to maximize translatability. To ensure that we achieve our goals, we have assembled a large cohort of experts in the field from multiple centers. Successful completion of the studies proposed will be a breakthrough, altering the 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 delineate the KC pathobiology and develop novel tools for its detection and treatment. Ultimately, the goal is to enable people with KC to live a normal life with little or no visual disability. The proposed work 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”.