FUNCTIONAL CHARACTERIZATION OF NR2E3 IN DEVELOPING AND ADULT PHOTORECEPTOR CELLS

NR2E3 在发育中和成年感光细胞中的功能特征

• 批准号: 8168359
• 负责人: Neena B Haider
• 金额: $ 5.84万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168359
• 关键词: Accounting; Adult; Affect; Biological; Blindness; Clinical; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Disease; Funding; Generations; Goals; Grant; Institution; Life; Maintenance; Modeling; Mus; Mutation; Nuclear Receptor Gene; Patients; Phenotype; Photoreceptors; Reporting; Research; Research Personnel; Resources; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Role; Source; Syndrome; United States National Institutes of Health; Vision; Visual impairment; emerging adult; improved; mouse model; novel; treatment strategy

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.

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。 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，这将使我们能够识别可能适合于改进治疗策略的新靶点。我们的研究集中在揭示核受体基因Nr2e3指导的转录网络，以调控光感受器的发育和功能。虽然过去的许多研究都集中在Nr2e3在发育中的视网膜中的作用，但它在成人视网膜中的高表达表明Nr2e3在成熟的光感受器细胞中也具有重要的功能。此外，最近的临床报告表明，Nr2e3基因的突变不仅导致增强型S视锥综合征(ESC)患者的视网膜变性，还导致1-2%的常染色体显性遗传性视网膜色素变性，该疾病通常会在成年早期导致严重的视力障碍，在生命的第四或第五个十年进展到严重的视力受限或失明。我们假设，虽然RD7小鼠是过度的蓝色锥体细胞导致ESCS表型的一个很好的模型，但本研究中产生的Nr2e3-Crerho小鼠可能提供一个更好的模型来概括Nr2e3相关的视网膜色素变性和由于成熟视网膜中Nr2e3功能丧失而导致的视网膜退化。有了这个新的小鼠模型，我们能够在不影响视网膜发育的情况下研究与成年光感受器细胞Nr2e3丢失相关的缺陷。因此，我们修改了这一应用，以关注Nr2e3在成熟视网膜中的作用，并确定成熟视网膜中Nr2e3丢失对RD7表型的影响程度。