FUNCTIONAL CHARACTERIZATION OF NR2E3 IN DEVELOPING AND ADULT PHOTORECEPTOR CELLS

该子项目是利用 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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 我们的长期目标是了解光感受器产生和维持的生物学机制，这将使我们能够确定可能适合改进治疗策略的新靶点。我们的研究主要集中在揭示核受体基因Nr 2 e3调控感光细胞发育和功能的转录网络。虽然许多过去的研究集中在Nr 2 e3在发育中的视网膜中的作用，但其在成人视网膜中的高表达表明Nr 2 e3在成熟的感光细胞中也具有重要功能。此外，最近的临床报告已经证明，Nr 2 e3中的突变不仅解释了在具有增强的S-视锥综合征（ESCS）的患者中观察到的视网膜变性，而且还解释了1-2%的常染色体显性视网膜色素变性，所述常染色体显性视网膜色素变性是一种通常在成年早期导致严重视力损害的疾病，所述疾病在生命的第四或第五个十年进展为严重视力受限或失明。我们假设，虽然rd 7小鼠作为一个很好的模型，过量的蓝锥细胞有助于ESCS表型，Nr 2 e3-Crerho小鼠产生的本研究可能提供了一个更好的模型，重演Nr 2 e3相关的视网膜色素变性和视网膜变性，由于Nr 2 e3功能的丧失，在成熟的视网膜。通过这种新的小鼠模型，我们能够研究与成年感光细胞中Nr 2 e3缺失相关的缺陷，而不影响视网膜发育。因此，我们修改了本申请集中在Nr 2 e3在成熟的视网膜中的作用，并确定在何种程度上的损失Nr 2 e3在成熟的视网膜有助于rd 7表型。

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. Our long-term goal is to understand the biological mechanisms of photoreceptor generation and maintenance, which will enable us to identify novel targets that may be amenable for improved treatment strategies. Our studies have focused on uncovering the transcriptional networks that are directed by the nuclear receptor gene Nr2e3 to modulate photoreceptor development and function. While many past studies have focused on the role of Nr2e3 in the developing retina, its high expression in the adult retina suggests an important function for Nr2e3 in mature photoreceptor cells as well. Furthermore, recent clinical reports have demonstrated that mutations in Nr2e3 not only account for the retinal degeneration observed in patients with enhanced S-cone syndrome (ESCS), but also account for 1-2% of autosomal dominant retinitis pigmentosa, a disease that typically leads to severe visual impairment in early adulthood progressing to severely limited vision or blindness by the fourth or fifth decade of life. We hypothesize that while the rd7 mouse serves as a good model for the excess blue cone cells contributing to the ESCS phenotype, the Nr2e3-Crerho mouse generated for this current study may provide a better model to recapitulate Nr2e3-associated retinitis pigmentosa and retinal degeneration due to loss of Nr2e3 function in the mature retina. With this new mouse model, we are able to study the defects associated with loss Nr2e3 in adult photoreceptor cells without affecting retinal development. We have thus revised this application to focus on the role of Nr2e3 in the mature retina and determine the extent to which loss of Nr2e3 in the mature retina contributes to the rd7 phenotype.