Sex disparity and estradiol in Fuchs' endothelial corneal dystrophy

项目摘要/摘要 Fuchs内皮性角膜营养不良(FECD)是导致女性角膜失明的主要原因之一 和男性一样频繁。角膜移植在FECD中恢复视力是成功的，但受到以下限制 世界许多地区供体组织的并发症和可获得性。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是制定有效的 替代预防和治疗战略。FECD上有限的年龄和性别分层数据表明 FECD在女性中的发病率在绝经后年龄组达到高峰，而在男性中保持稳定。 因为这个年龄段的女性的血清雌二醇水平变化很大，所以 本研究认为雌激素通过雌激素受体β(ERβ)对角膜内皮细胞有保护作用。这个 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。这个指导职业奖的目标是 Sangita Patel，医学博士，博士将使她具备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(医学博士、博士、生理学、布法罗大学)和临床方面的科学专长 角膜方面的专业知识(梅奥诊所眼科住院医师；马萨诸塞州眼耳科眼科研究员 医务室)构成了开发FECD新疗法的理想领导者的框架。为了成功 继续这条道路，Patel博士对K08职业发展奖有三个主要目标：1.了解 临床和流行病学研究设计原则，以便有效地与流行病学家合作 进行有效设计的研究；2.学习基础科学和流行病学研究的基本生物统计学 申请；及3.建立成功的协作关系，使她能够领导她的临床和 科学背景。解决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)； 在她的指导团队(领导)的支持下，出版、演示和启动协作研究 眼科研究和流行病学)；以及3.NIH R01作为独立的 四年级的调查员。她将在多样化、激动人心的协作环境中从事这些活动 在布法罗大学。这个应用程序的具体目的是为了检验中心假设 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，并评估雌激素暴露与FECD严重程度之间的关系。 特异目的2是确定雌激素和雌激素受体β在调节机体对氧化应激反应中的作用。 角膜内皮。这些研究的结果将为临床流行病学研究提供科学依据。 支持FECD治疗靶向雌二醇途径的重大未来进展的数据。

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.