Sex disparity and estradiol in Fuchs' endothelial corneal dystrophy

项目概要/摘要 福克斯内皮性角膜营养不良 (FECD) 是导致女性角膜失明的主要原因 和男性一样频繁。角膜移植可成功恢复 FECD 患者的视力，但受到以下因素的限制： 世界许多地区的并发症和供体组织的可用性。这项研究的长期目标是 开发 FECD 的药物治疗和预防策略，以减少移植的需要。 了解 FECD 患病率性别差异的基础对于制定有效的 替代的预防和治疗策略。 FECD 有限的年龄和性别分层数据表明 女性 FECD 的发病率在绝经后年龄组达到高峰，而男性则保持稳定。 由于该年龄段女性的血清雌二醇水平发生显着变化，因此中心假说 这项研究表明雌二醇通过雌激素受体β（ERβ）保护角膜内皮。的 绝经后雌二醇减少导致角膜内皮代谢应激增加，表现为 与男性相比，女性 FECD 的严重程度更高。该指导职业奖的目标是 Sangita Patel 博士将为她提供领导流行病学和实验室研究所需的技能 在FECD上。 Patel 博士在生理学（布法罗大学医学博士、博士、生理学）和临床方面的科学专业知识 角膜专业知识（梅奥诊所眼科住院医师实习；马萨诸塞州眼耳科角膜研究金 医务室）构成了开发 FECD 新疗法的理想领导者的框架。才能成功 继续这条道路，帕特尔博士为 K08 职业发展奖设定了三个主要目标： 1. 学习 临床和流行病学研究设计原则，以便与流行病学家有效合作 进行有效设计的研究； 2.学习基础科学和流行病学研究所必需的生物统计学 应用程序；和。 3.建立成功的合作关系，使她能够领导她的临床和 科学背景。实现这些目标的职业发展计划的关键要素是： 1. 通过教学和实际应用发展研究技能（流行病学和生物统计学）； 2. 在她的指导团队（领导者）的支持下发表出版物、演讲和启动合作研究 眼科研究和流行病学）； 3. 作为独立人士提交 NIH R01 申请 第四年的调查员。她将在多样化、刺激的协作环境中开展这些活动 在布法罗大学。该应用程序的具体目标旨在检验中心假设 并涵盖职业发展目标。具体目标 1 是确定年龄对性别的影响 FECD 患病率的差异，并评估雌激素暴露与 FECD 严重程度之间的关联。 具体目标 2 是确定雌二醇和 ERβ 在调节氧化应激反应中的作用 角膜内皮。这些研究的结果将为科学和临床流行病学提供依据。 数据支持未来针对 FECD 疗法靶向雌二醇途径的重大进展。

PROJECT SUMMARY/ABSTRACT Fuchs' endothelial corneal dystrophy (FECD) is a leading cause of corneal blindness that affects females twice as often as males. Corneal transplantation is successful at restoring vision in FECD, but is limited by complications and availability of donor tissue in many parts of the world. The long term goal of this research is to develop drug therapies and preventive strategies for FECD to decrease the need for transplantation. Understanding the basis for the sex disparity in prevalence of FECD is necessary to develop effective alternative preventive and treatment strategies. The limited age and sex stratified data on FECD suggest that the incidence of FECD in females peaks in the postmenopausal age group while remaining stable in males. Because levels of serum estradiol change dramatically in women of this age group, the central hypothesis of this study is that estradiol protects the corneal endothelium via estrogen receptor beta (ERβ). The postmenopausal decrease in estradiol leads to increased corneal endothelial metabolic stress that manifests as increased severity of FECD in females compared to males. The goal of this mentored career award to Sangita Patel, MD, PhD is to equip her with the skills necessary to lead epidemiologic and laboratory research on FECD. Dr. Patel's scientific expertise in physiology (MD, PhD, Physiology, Univ at Buffalo) and clinical expertise in cornea (ophthalmology residency, Mayo Clinic; cornea fellowship, Massachusetts Eye and Ear Infirmary) form the framework for an ideal leader for developing novel treatments for FECD. To successfully continue this path, Dr. Patel has three primary objectives for the K08 career development award: 1.To learn the principles of clinical and epidemiologic study design in order to effectively collaborate with epidemiologists to conduct validly designed studies; 2.To learn essential biostatistics for basic science and epidemiology research applications; and. 3.To build successful collaborative relationships in which she can lead with her clinical and scientific background. Key elements of the career development plan to address these objectives are: 1. Research skills development (epidemiology and biostatistics) through didactics and practical application; 2. Publications, presentations, and initiation of collaborative studies with support by her mentoring team (leaders in ophthalmic research and epidemiology); and 3. Submission of a NIH R01 application as an independent investigator in Year 4. She will undertake these activities in the diverse, stimulating collaborative environment at the University at Buffalo. The Specific Aims of this application are designed to test the central hypothesis and encompass the career development goals. Specific Aim 1 is to determine the effect of age on the sex disparity of FECD prevalence and to evaluate the association between estrogen exposure and FECD severity. Specific Aim 2 is to determine the roles of estradiol and ERβ in regulating the response to oxidative stress in the corneal endothelium. The outcomes of these studies will provide the scientific and clinical epidemiologic data to support significant future advances toward targeting estradiol pathways for FECD therapeutics.