Sex disparity and estradiol in Fuchs' endothelial corneal dystrophy

项目总结/摘要 富克斯角膜内皮营养不良（FECD）是角膜失明的主要原因，影响女性两次 和男性一样多角膜移植在恢复FECD患者的视力方面是成功的，但受到以下因素的限制： 并发症和供体组织的可用性在世界许多地方。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流行率的性别差异的基础对于制定有效的 替代预防和治疗策略。有限的关于FECD的年龄和性别分层数据表明， 女性FECD的发生率在绝经后年龄组达到峰值，而男性保持稳定。 因为血清雌二醇水平在这个年龄组的妇女中变化很大， 本研究认为雌二醇通过雌激素受体β（ERβ）对角膜内皮细胞具有保护作用。的 绝经后雌二醇减少导致角膜内皮代谢应激增加， 与男性相比，女性FECD的严重程度增加。这个指导性职业奖的目标是 桑吉塔帕特尔，医学博士，博士是装备她所需的技能，领导流行病学和实验室研究 关于FECD Patel博士在生理学（医学博士，博士，生理学，布法罗大学）和临床方面的科学专长 角膜专业知识（马约诊所眼科住院医师;马萨诸塞州眼耳医院角膜奖学金 医务室）形成了一个理想的领导者开发FECD新疗法的框架。成功 继续这条道路，帕特尔博士有三个主要目标的K 08职业发展奖：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需的生物统计学 应用;及。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. 出版物，演讲，并在她的指导团队（领导者）的支持下启动合作研究 在眼科研究和流行病学）;和3.提交NIH R 01申请作为独立的 四年级的调查员。她将在多样化、激励性的协作环境中开展这些活动 在布法罗大学。本申请的具体目的旨在检验中心假设 并包含职业发展目标。具体目标1是确定年龄对性别的影响 FECD患病率的差异，并评估雌激素暴露和FECD严重程度之间的关系。 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提供科学和临床流行病学 数据支持未来FECD治疗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.