Genotype-Phenotype Correlations in Primary Congenital Glaucoma

描述（由申请人提供）：PI（Yanovitch博士）目前由K12机制资助。该提案概述了3年3个月的研究持续，共6年的职业发展资金，以继续指导临床研究目标。杜克眼科中心和杜克大学（培训地点）是出色的培训环境，拥有众多的资源、互动、设施和独特的学习机会。杜克坚定地致力于培养和支持下一代临床科学家。这项研究计划涉及的方法，如统计建模，眼部成像和基因分型，旨在预测难治性原发性先天性青光眼（PCG）的发展。主要项目将是检验由基线临床特征和解剖学发现定义的表型准确预测预后以及这些表型与基因型发现正相关的假设。在接下来的31/4年里，我们（PI及其团队）将实现以下目标：1）继续建立PCG队列数据库，并确定来自美国多个研究中心的PCG患者的DNA样本， 2)开发并验证难治性青光眼的预后模型，以定义表型，3）进行病例对照试验，比较正常、轻度青光眼和难治性PCG受试者的房角结构，以及4）基于先前定义的表型进行基因型-表型相关性。我们希望这些研究将证实我们提出的临床分类系统和影像学结果，以及提供证据支持基因型-表型相关性。这些初步数据的目的是证明一项正式的、前瞻性的、多中心的研究，以验证我们通过R 01资助的研究结果。PI的长期职业目标是将相同的分析方法应用于其他复杂的，具有遗传成分的儿科眼科疾病，如早产儿视网膜病变和斜视。PI致力于治疗遗传性儿科眼病和知识的进步。作为K12计划的一部分，PI已经完成了临床研究健康科学硕士的课程要求。在短期内，PI希望继续发展她的基础科学知识基金，开发成像和分析眼前节的协议，并继续指导涉及临床遗传学的研究，以便为独立研究奠定坚实的基础。 公共卫生相关性：本研究的重点是原发性先天性青光眼（PCG），这是一种影响婴儿和3岁以下儿童视力的疾病。PCG背后的具体结构和分子机制仍然知之甚少。通过将精确的临床研究方法与尖端的诊断和基因分型技术相结合，这项研究将开发工具，以帮助更早地诊断和治疗PCG，并采取更有针对性的干预措施。

DESCRIPTION (provided by applicant): The PI (Dr. Yanovitch) is currently funded by a K12 mechanism. This proposal outlines a 3 year, 3 month continuation of research, for a total of 6 years of career development funding, in order to continue mentored clinical research aims. Duke Eye Center and Duke University (sites of training) are outstanding training environments with numerous resources, interactions, facilities, and unique learning opportunities. Duke has made a strong commitment to training and supporting the next generation of clinician scientists. This research proposal involves the development of methods, such as statistical modeling, ocular imaging and genotyping, designed to predict refractory primary congenital glaucoma (PCG). The main project will be to test the hypothesis that phenotypes defined by baseline clinical characteristics and anatomic findings accurately predict prognosis and that these phenotypes positively correlate with genotypic findings. Over the next 31/4 years, we (the PI and her team) will accomplish the following objectives: 1) continue establishing a PCG cohort database and ascertaining DNA samples from PCG patients from multiple sites throughout the U.S., 2) develop and validate a prognostic model for refractory glaucoma in order to define phenotypes, 3) conduct a case-control trial comparing angle structures in normal, mild glaucoma, and refractory PCG subjects, and 4) perform genotype-phenotype correlations based upon previously defined phenotypes. We expect that these studies will confirm our proposed clinical classification system and imaging findings, as well as provide evidence to support genotype-phenotype correlations. The goal for this preliminary data is to justify a formal, prospective, multi-center study to validate our findings funded through an R01. The PI's long- term career goal is to apply the same analytic approach to other complex, pediatric eye diseases with a genetic component like retinopathy of prematurity and strabismus. The PI has committed her career to the treatment of genetic pediatric eye diseases and to the advancement of knowledge. As part of the K12 program, the PI has completed the course requirements for a Master's of Health Sciences in Clinical Research. In the short term, the PI hopes to continue to grow her basic sciences fund of knowledge, develop protocols for imaging and analyzing the anterior segment, and continue mentored research involving clinical genetics in order to obtain a solid foundation for independent research. PUBLIC HEALTH RELEVANCE: This study focuses on primary congenital glaucoma (PCG), a sight-threatening condition affecting infants and children from birth to 3 years of age. The specific structural and molecular mechanism behind PCG remains poorly understood. By combining precise clinical research methodology with cutting-edge diagnostic and genotyping techniques, this study will develop tools to help diagnose and treat PCG earlier with better targeted interventions.