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

圆锥角膜、性激素和垂体前叶之间的密切相互作用

• 批准号: 10746247
• 负责人: Dimitrios Karamichos
• 金额: $ 39.35万
• 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: 2023-09-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746247
• 关键词: 3-Dimensional; Adrenal Glands; Affect; Age; Androgens; Anterior Pituitary Gland; Area; Astigmatism; Basic Science; Biochemical; Biological Markers; Blindness; Blood; Cell physiology; Cells; Cicatrix; Circulation; Clinical; Collagen; Complex; Contact Lenses; Cornea; Corneal Diseases; Corneal Stroma; Data; Detection; Development; Diagnosis; Disease; Down-Regulation; Endocrine; Equilibrium; Estriol; Estrogens; Estrone; Etiology; Eye Injuries; Eye diseases; Feedback; Fibrosis; Follicle Stimulating Hormone; Functional disorder; Funding; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Health; Hormonal; Hormone Receptor; Hormone secretion; Hormones; Human; Hypothalamic structure; In Vitro; Investigation; Keratoconus; Keratoplasty; Knowledge acquisition; Legal patent; Life; Link; Luteinizing Hormone; Measures; Mediating; Metabolism; Mitochondria; Monitor; Myopia; Operative Surgical Procedures; Pathogenesis; Patient Care; Patients; Persons; Pituitary Gland; Plasma; Population; Prevention; Prolactin; Proteins; Public Health; Publishing; Race; Recovery; Recurrence; Reporting; Research; Research Priority; Role; Saliva; Same-sex; Sampling; Severities; Shapes; Signal Transduction; Stromal Cells; Teenagers; Thinness; Time; Tissues; Up-Regulation; Variant; Vision; Visual; Visual impairment; Work; clinically relevant; cohort; crosslink; dehydroepiandrosterone; design; disability; hypothalamic pituitary gonadal axis; improved; in vitro Model; in vivo; insight; mitochondrial genome; novel; novel diagnostics; ocular surface; pregnant; prevent; programs; receptor; sex; tool

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”.

项目总结/摘要 圆锥角膜（KC）是一种进行性、非炎性的角膜扩张性疾病，其特征是角膜变陡 以及角膜变薄、不规则散光、近视和疤痕。尽管引入了角膜 由于交联阻止进展和巩膜接触透镜设计的改进， 治疗KC的圣杯KC是目前导致角膜移植的最常见适应症之一。 此外，现在有越来越多的证据表明，KC复发，即使在角膜移植。迄今为止， KC的病因和发病机制仍不清楚，包括复发的原因。因此，有一个 迫切需要了解和定义KC的发作/进展。我们的团队正在带领KC研究 性激素和促性腺激素，这将为一个在很大程度上被忽视的话题提供有价值的贡献 尽管临床观察和发现。我们的小组报告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）的研究，发现KC中存在促性腺激素及其受体。是 因此公平地问，“什么是促性腺激素在人类角膜和KC的作用？”和“是否有一个功能性的 这些促性腺激素及其受体的作用，可以解释KC病理生物学？我们的初步数据显示 许多人认为的“所有激素之王”，促性腺激素释放激素（GnRH）， 与健康对照组相比。GnRH受体（GnRH-R）存在于KC基质细胞中， 促黄体生成素（LH）促性腺激素。LH和卵泡刺激素（FSH），反过来，调节 性腺和肾上腺性激素（脱氢表雄酮-DHEA，雌酮和雌三醇）先前显示， 我们在KC中不平衡。这些同性激素在角膜移植后被系统地调节， 交联总之，我们的数据表明，KC高度依赖于以下因素的平衡和相互作用： 促性腺激素和性激素。具体来说，我们假设激素分泌异常是 与FSH和LH相关，随后是性激素失调，最终影响角膜 微环境介导KC发作和进展。目前的建议旨在使调查结果 在体外、离体和体内都得到了验证，以最大限度地提高可翻译性。为了确保我们实现我们的 为了实现这些目标，我们从多个中心召集了该领域的大量专家。成功完成 这项研究的提出将是一个突破，改变目前的标准护理与KC患者。 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。有 迫切需要描述KC病理生物学并开发用于其检测和治疗的新工具。 最终，我们的目标是使KC患者能够过上正常的生活，很少或没有视力残疾。拟议 工作是翻译的，临床相关的，并符合NEI的计划目标：“应用所获得的知识 从角膜和其他眼表组织的基础科学的发现到诊断， 预防和治疗眼部损伤和疾病”。