FUNCTIONAL CHARACTERIZATION OF NR2E3 IN DEVELOPING AND ADULT PHOTORECEPTOR CELLS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 视觉也许是我们感知环境的最重要的感觉。 视力障碍影响着全球1亿多人，其中大多数疾病是遗传性的;只有不到3%是由创伤或感染引起的[1]。 这些眼部疾病的很大一部分导致视网膜损伤，影响视网膜发育或功能。此外，尽管临床上已经鉴定了超过300种视网膜疾病[2，3]，但并非所有与人类疾病相关的基因都是已知的，也没有足够的模型系统可用于研究这些疾病。模型系统的开发，以及视网膜疾病进展过程中被破坏的生物学途径的全面表征，将使我们能够了解视网膜遗传损伤的分子性质，疾病表现变化的原因，以及最终如何治疗，预防和治愈。 本申请侧重于了解转录因子Nr 2 e3在发育和成人视网膜中的作用。Nr 2 e3是类固醇激素核受体转录因子家族的一部分，这些转录因子通常被配体激活，并具有许多相似的结构基序，这些结构基序对直接蛋白质相互作用和DNA结合能力很重要[4-6]。Nr 2 e3是已知参与指导感光细胞生成和成熟视网膜建立的少数基因之一[手稿在准备中]。 虽然我们对Nr 2 e3有一定的了解？由于它在感光细胞发育中的作用，我们并不完全了解它是如何发挥作用的，它的下游靶点是什么，或者它是如何被调节的。人Nr 2 e3突变与S-视锥细胞增强综合征（ESCS）相关，其特征为视网膜变性和S-视锥细胞超敏反应[7，8]，而小鼠Nr 2 e3突变与视网膜变性7（rd 7）小鼠相关[9，10]。ESCS是唯一已知的视网膜营养不良，表现为光感受器亚型的功能获得。rd 7小鼠提供了一个独特的模型来研究细胞生成和导致视网膜变性的这一过程的中断。本提案的目的是确定Nr 2 e3在发育和成人视网膜中的作用。

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.