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

基本信息

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
项目类别：
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

项目摘要

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”.

项目概要/摘要圆锥角膜 (KC) 是一种进行性、非炎症性扩张性角膜疾病，其特征是角膜变陡尽管引入了角膜，但角膜变薄，不规则散光，近视和疤痕。交联以阻止进展并改进巩膜隐形眼镜设计，角膜移植仍然存在治疗 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，现在越来越多的证据表明 KC 即使在角膜移植后也会复发。 KC 的病因和发病机制尚不清楚，包括复发的原因。迫切需要了解和定义 KC 的发生/进展我们小组正在带头进行 KC 研究。性激素和促性腺激素，这将为一个很大程度上被忽视的话题提供有价值的贡献尽管有临床观察和发现，我们的小组报告了一种新型性激素调节的 KC 生物标志物，催乳素诱导蛋白（PIP），并发现 KC 中促性腺激素及其受体的存在。因此，我们可以问“促性腺激素在人类角膜和 KC 中的作用是什么？”以及“是否存在功能性作用”。这些促性腺激素及其受体的作用可以解释 KC 病理学吗？”我们的初步数据显示。许多人认为“所有激素之王”促性腺激素释放激素 (GnRH) 的失调与健康对照相比，KC 受体 (GnRH-R) 存在于 KC 基质细胞中并受到调节。黄体生成素 (LH) 、促性腺激素 (FSH) 又受促性腺激素 (FSH) 调节。性腺和肾上腺性激素（脱氢表雄酮-DHEA、雌酮和雌三醇）我们的 KC 不平衡，这些相同的性激素根据角膜进行系统调节。总之，我们的数据表明 KC 高度依赖于以下物质的平衡和相互作用。具体来说，我们认为荷尔蒙分泌异常是。与 FSH 和 LH 相关，然后是性激素失调，最终影响角膜介导 KC 发生和进展的微环境目前的提案旨在使研究结果得以实现。在体外、离体和体内进行验证，以确保我们实现我们的可翻译性。为了实现这一目标，我们聚集了来自多个中心的一大批该领域的专家。拟议的研究将是一项突破，改变目前 KC 患者的护理标准。与公共卫生的相关性——KC 是导致全球视力障碍的一个主要临床问题。迫切需要描述 KC 病理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障碍。工作是转化性的、临床相关的，并且符合 NEI 的项目目标：“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， “眼损伤和疾病的预防和治疗”。