Defining the genetic landscape of nanophthalmos and the role of MYRF

定义纳米眼球的遗传景观和 MYRF 的作用

基本信息

批准号：
10558740
负责人：
Lev Prasov
金额：
$ 23.01万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558740
关键词：
Affect Alleles Amblyopia Angle-Closure Glaucoma Animal Model Area Basic Science Binding Bioinformatics Biological Biological Assay Biology Blindness Candidate Disease Gene Cardiac Cell Culture Techniques Cell Death Child Code Collaborations DNA Data Defect Development Developmental Biology Disease Environment Eye Eye Development Eye diseases Family Foundations Functional disorder Future Gene Expression Profile Gene Targeting Genes Genetic Genetic Diseases Genetic Heterogeneity Genetic Transcription Genitourinary system Genomics Genotype Goals Growth Heritability Heterogeneity Human Hyperopia Impairment In Vitro Inheritance Patterns Inherited Institution Investigation Knock-in Mouse Knockout Mice Knowledge Laboratories Lead Learning Length Link Medical Mentors Microphthalmos Modeling Molecular Molecular Diagnosis Molecular Target Morphology Mus Myelin Myopia N-terminal National Eye Institute Ophthalmology Outcome Pathogenesis Pathologic Pathway interactions Patient Care Patients Pattern Phenotype Physiological Public Health Reagent Refractive Errors Research Research Personnel Retina Retinal Degeneration Role Sampling Scientist Secondary to Serous Strabismus Structure Structure of retinal pigment epithelium System Techniques Testing Tissues Training Transcriptional Activation Transcriptional Regulation Validation Variant Vision Visual Fields Visual impairment Work analysis pipeline autosome candidate identification career development clinical heterogeneity clinical practice cohort conditional knockout de novo mutation design developmental genetics disease mechanisms study disease phenotype experience gene discovery genetic variant genome sequencing genomic locus human disease improved in silico innovation insight large datasets mouse model novel novel therapeutics overexpression recruit single-cell RNA sequencing skills targeted treatment transcription factor whole genome

项目摘要

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.

定义纳米眼球的遗传景观和 MYRF 的作用抽象的：纳米眼球是一系列以小眼睛和由此导致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、弱视以及浆液性视网膜和脉络膜分遣队。这种情况的发病机制尚不清楚，但遗传因素被认为是一个因素强有力的贡献者。我发现了一种新的人类疾病基因，即家族性纳米眼球，髓鞘质调节基因因子（MYRF），它也会导致小鼠视网膜变性和视网膜色素上皮（RPE）破坏。该基因编码多效性转录因子，与多系统疾病有关具有心脏、泌尿生殖系统缺陷和高度远视的特征。我的提案的主要目标是：（i）确定 MYRF 在眼睛中的分子靶标； (ii) 定义 MYRF 破坏导致的机制人类疾病和 RPE 功能障碍； (iii) 确定高发病机制的新遗传因素远视。我的首要假设是 MYRF 作为 RPE 分化的主要调节器，并且 MYRF 关键下游靶点的破坏也会通过破坏 RPE 导致纳米眼球结构和/或功能。该假设将通过以下方式进行检验：（i）确定 MYRF 的分子靶点通过单细胞RNA测序和CUT&RUN测序； (ii) 定义临床和遗传高度远视和纳米眼球家族的异质性。我的长期目标是成为独立临床研究者，专注于识别和治疗遗传性眼部疾病，以及了解分子发病机制。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、一名眼科医生临床医生科学家、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，重点关注教学和实践经验。和这个团队一起和强大的制度环境，我将接受发育生物学、生物信息学和基因组学方面的培训，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成为眼科遗传学领域领先的临床医生科学家，并且提供我的临床实践和基础科学研究之间的直接联系。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。这该提案将深入了解调节 RPE 发育的新途径，并确定可调节 RPE 发育的新基因调节眼睛的生长，这将成为未来研究的一个重要的新领域。