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.