Defining the genetic landscape of nanophthalmos and the role of MYRF

定义小眼球的遗传景观和MYRF的作用 摘要： 小眼球是一系列以小眼睛和由此产生的高度远视为特征的疾病的一部分。它 常并发闭角型青光眼、斜视、弱视和浆液性视网膜和脉络膜 冷静这种情况的发病机制知之甚少，但遗传因素被认为是一个重要的因素。 强大的贡献者。我已经确定了一个新的人类疾病基因的家族性小眼球，髓鞘调节 在小鼠中，MYRF也导致视网膜变性和视网膜色素上皮（RPE）破坏。 该基因编码一种多效性转录因子，并与多系统疾病有关 表现为心脏泌尿生殖缺陷和高度远视我的建议的主要目标是：（一）确定 MYRF在眼睛中的分子靶点;（ii）定义MYRF破坏导致 人类疾病和RPE功能障碍;和（iii）鉴定高视网膜病变发病机制的新的遗传贡献者。 远视我的过度假设是MYRF是RPE分化的主要调节因子， MYRF关键下游靶点的破坏也会通过破坏RPE而导致小眼球 结构和/或功能。这一假设将通过以下方式进行检验：（i）确定多年期研究框架的分子靶点 通过单细胞RNA测序和CUT&RUN测序;和（ii）定义临床和遗传 高度远视和小眼球家族的异质性。我的长期目标是成为一名 专注于识别和治疗遗传性眼部疾病的独立临床研究者，以及 了解分子发病机理。为了实现这一目标，我组建了一个导师团队， 具有相关专业知识的合作者;该团队包括一名发育遗传学家，一名眼科医生， 临床科学家，医学遗传学家，基因组学和生物信息学专家。我和我的导师们 制定了一个结构化的培训计划，重点是教学和实践经验。和这个团队一起 和一个强大的机构环境，我将在发育生物学，生物信息学和基因组学， 这些都是我的专业发展和完成本提案所必需的。这个职业 发展轨迹将使我发展成为眼科遗传学领域领先的临床科学家， 在我的临床实践和我的基础科学研究之间提供直接联系。它还将为我提供 完成基因发现的完整周期的技能，这可能对患者护理产生直接影响。这 该提案将导致对调节RPE发育的新途径的深入了解，并确定新基因， 调节眼睛生长，这将建立一个关键的新领域的未来研究。

Defining the genetic landscape of nanophthalmos and the role of MYRF ABSTRACT: Nanophthalmos is part of a spectrum of disorders characterized by a small eye and resultant high hyperopia. It is frequently complicated by angle closure glaucoma, strabismus, amblyopia, and serous retinal and choroidal detachments. The pathogenesis of this condition is poorly understood, but genetic factors are thought to be a strong contributor. I have identified a novel human disease gene for familial nanophthalmos, myelin regulatory factor (MYRF), which also leads to retinal degeneration and retinal pigment epithelial (RPE) disruption in mice. This gene encodes a pleiotropic transcription factor and has been implicated in a multi-system disorder featuring cardiac, urogenital defects, and high hyperopia. The primary goals of my proposal are to: (i) identify the molecular targets of MYRF in the eye; (ii) define the mechanism by which disruption of MYRF leads to human disease and RPE dysfunction; and (iii) identify novel genetic contributors to the pathogenesis of high hyperopia. My over-arching hypothesis is that MYRF serves as a master regulator of RPE differentiation, and that disruption of key downstream targets of MYRF also leads to nanophthalmos by disrupting RPE structure and/or function. This hypothesis will be tested by: (i) determining the molecular targets of MYRF through single-cell RNA sequencing and CUT&RUN sequencing; and (ii) defining the clinical and genetic heterogeneity in families with high hyperopia and nanophthalmos. My long-term goal is to become an independent clinician investigator who focuses on identifying and treating inherited ocular disorders, and understanding molecular pathogenesis. To facilitate this goal, I have assembled a team of mentors and collaborators with relevant expertise; this team includes a developmental geneticist, an ophthalmology clinician-scientist, a medical geneticist, and an expert in genomics and bioinformatics. My mentors and I have developed a structured training plan focused on didactic and hands-on experience. Together with this team and a strong institutional environment, I will train in developmental biology, bioinformatics, and genomics, which are all required for my professional development and completion of this proposal. This career development trajectory will allow me to develop into a leading clinician-scientist in ophthalmic genetics, and provide a direct link between my clinical practice and my basic science research. It also will provide me with the skills to complete full cycles of gene discovery, which can have direct implications on patient care. This proposal will lead to insights into a novel pathway regulating RPE development and identify novel genes that regulate eye growth, which will establish a critical new area of future investigation.