FUNCTIONAL CHARACTERIZATION OF NR2E3 IN DEVELOPING AND ADULT PHOTORECEPTOR CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 视觉可能是我们感知环境的最关键的感觉。视力障碍影响全球1亿多人，其中大多数是遗传性疾病；只有不到3%的疾病是由创伤或感染引起的[1]。这些眼病中的很大一部分会导致视网膜损伤，影响视网膜的发育或功能。此外，尽管临床上已经确定了300多种视网膜疾病[2，3]，但并不是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来研究这些疾病。模型系统的发展，以及对视网膜疾病进展过程中被破坏的生物通路的全面表征，将使我们能够了解视网膜遗传侮辱的分子本质，疾病表现的差异的原因，以及最终如何治疗、预防和治愈这些疾病。 这项应用侧重于了解转录因子Nr2e3在发育和成年视网膜中的作用。Nr2e3是类固醇激素核受体转录因子家族的一部分，通常是配体激活的，具有许多相似的结构基序，对于直接蛋白质相互作用和DNA结合能力非常重要[4-6]。Nr2e3是为数不多的几个已知的基因之一，参与指导光感受器细胞的产生和成熟视网膜的建立[手稿正在准备中]。虽然我们对Nr2e3、S在光感受器发育中的作用有一定的了解，但我们还不清楚它是如何发挥作用的，它的下游靶点是什么，或者它是如何被调控的。人类Nr2e3的突变与增强型S视锥综合征(ESCs)有关，增强型ESC的特征是视网膜变性和S视锥细胞过敏[7，8]，而小鼠Nr2e3的突变与视网膜变性7(RD7)小鼠[9，10]有关。ESCs是唯一已知的表现为光感受器亚型功能获得的视网膜营养不良。Rd7小鼠提供了一种独特的模型来研究细胞的产生和破坏这一导致视网膜退化的过程。这项建议的目的是确定Nr2e3在发育中的视网膜和成年视网膜中所扮演的角色。

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.