This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sight is perhaps the most crucial sense by which we perceive the environment. Visual impairment affects over 100 million people worldwide and most of these diseases are genetic in nature;with less than 3% resulting from trauma or infection [1]. A significant portion of these ocular diseases result in damage to the retina either affecting retinal development or function. In addition, although over 300 varieties of retinal diseases have been clinically identified [2,3], not all of the genes associated with the human diseases are known nor are there sufficient model systems available to study these diseases. The development of model systems, and comprehensive characterization of biological pathways disrupted during retinal disease progression, will enable us to understand the molecular nature of genetic insults to the retina, the causes of variation in manifestation of diseases, and ultimately how they may be treated, prevented, and cured. This application focuses on understanding the role of the transcription factor Nr2e3 in the developing and adult retina. Nr2e3 is part of the steroid hormone nuclear receptor family of transcription factors that are generally ligand activated and share many similar structural motifs that are important for direct protein interactions and DNA binding capabilities [4-6]. Nr2e3 is one of a few genes known to be involved in directing photoreceptor cell generation and establishment of the mature retina [manuscript in preparation]. While we do have some knowledge of Nr2e3?s role in photoreceptor development, we do not have thorough knowledge of how it functions, what are its downstream targets, or how it is regulated. Mutations in human Nr2e3 are associated with Enhanced S-cone syndrome (ESCS), which is characterized by retinal degeneration and hypersensitivity of S-cones [7,8], while mutations in mouse Nr2e3 are associated with the retinal degeneration 7 (rd7) mouse [9,10]. ESCS is the only known retinal dystrophy that manifests as a gain of function in a photoreceptor subtype. The rd7mouse provides a unique model to study cell generation and disruption of this process leading to retinal degeneration. The purpose of this proposal is to determine the role that Nr2e3 plays in both the developing and the adult retina.
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