Sex disparity and estradiol in Fuchs' endothelial corneal dystrophy

福克斯内皮性角膜营养不良中的性别差异和雌二醇

• 批准号: 9505347
• 负责人: Sangita Patel
• 金额: $ 17.1万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9505347
• 关键词: Address; Affect; Age; Agonist; Award; Basement membrane; Basic Science; Bioenergetics; Biometry; Blindness; Bone Density; Buffaloes; Cell Culture Techniques; Cell physiology; Cellular Stress; Chronic; Clinic; Clinical; Clinical Research; Cohort Studies; Collaborations; Communities; Complement; Cornea; Corneal Endothelium; Cross-Sectional Studies; Data; Development; Development Plans; Disease; Doctor of Philosophy; Ear; Elements; Endothelial Cells; Environment; Epidemiologist; Epidemiology; Estradiol; Estradiol Receptors; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Eye; Family; Fellowship; Female; Fuchs' Endothelial Dystrophy; Functional disorder; Future; Gene Expression; Genes; Genetic; Goals; Gonadal Steroid Hormones; Health; Hormonal; Human; Incidence; Individual; Institutes; K-Series Research Career Programs; Keratoplasty; Knowledge; Laboratory Research; Lead; Learning; Link; Massachusetts; Measures; Mediating; Mentors; Metabolic stress; Mitochondria; Modeling; Molecular; Operative Surgical Procedures; Ophthalmology; Outcome Study; Oxidative Stress; Oxidative Stress Pathway; Participant; Pathway interactions; Patients; Pharmacotherapy; Physiology; Postmenopause; Prevalence; Prevention strategy; Preventive; Proxy; Public Health; Publications; Questionnaires; Research; Research Design; Research Personnel; Residencies; Respiration; Role; Science; Scientist; Serum; Severities; Severity of illness; Stress; Surgeon; Swelling; TCF7L2 gene; Testing; Therapeutic; Tissue Donors; Training; Transplantation; United States; United States National Institutes of Health; Universities; Vision; Woman; age effect; age group; burden of illness; career; career development; cell type; cohort; collaborative environment; design; epidemiologic data; epidemiology study; innovation; male; malignant breast neoplasm; metabolic profile; mitochondrial dysfunction; novel; practical application; prevent; response; sex; sex disparity; skill acquisition; skills; treatment strategy

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.

项目摘要/摘要 福克斯的内皮角膜营养不良（FECD）是角膜失明的主要原因，两次影响雌性 和男性一样。角膜移植成功地恢复了FECD的视觉，但受到限制 世界许多地方的并发症和供体组织的可用性。这项研究的长期目标是 制定药物疗法和FECD的预防策略，以减少移植的需求。 了解feCD患病率的性别差异的基础对于发展有效是必要的 替代预防和治疗策略。 FECD上的年龄和性别分层数据表明 fecd在雌性后年龄组中达到峰值，同时保持稳定的男性。 因为该年龄段的女性的血清雌二醇水平急剧变化，所以 这项研究是雌二醇通过雌激素受体β（ERβ）保护角膜植物。 绝经后雌二醇的减少导致角膜内皮代谢应激增加，表现出来 与男性相比，女性的FECD严重程度增加。这个修改职业奖的目标 医学博士桑吉塔·帕特尔（Sangita Patel）旨在为她提供领导流行病学和实验室研究所需的技能 在FECD上。帕特尔博士的生理学科学专业知识（MD，博士，生理学，布法罗大学）和临床 角膜的专​​业知识（Mayo诊所眼科住所；角膜奖学金，马萨诸塞州的眼睛和耳朵 医务室）构成了为FECD开发新型治疗方法的理想领导者的框架。成功 继续这条道路，帕特尔博士拥有K08职业发展奖的三个主要对象：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的基本生物统计学 申请；和。 3.建立成功的合作关系，在其中她可以领导自己的临床和 科学背景。解决这些目标的职业发展计划的关键要素是：1。 研究技能开发（流行病学和生物统计学）通过教学和实际应用； 2。 她的心理团队的支持（领导者 在眼科研究和流行病学上）；和3。提交NIH R01申请作为独立 第4年的调查员。她将在潜水员中进行这些活动，刺激协作环境 在布法罗大学。该应用程序的具体目的旨在检验中心假设 并包括职业发展目标。特定目标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。 具体目的2是确定雌二醇和ERβ在控制对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 数据以支持靶向雌二醇途径进行FECD疗法的重大进展。