Development of the HTS Assay for Agonists of the Orphan Nuclear Receptor NR2E3

孤儿核受体 NR2E3 激动剂的 HTS 测定的开发

• 批准号: 7426655
• 负责人: Konstantin Petrukhin
• 金额: $ 16.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426655
• 关键词: Adult; Age related macular degeneration; Agonist; Animal Model; Atrophic; Biological Assay; Biological Preservation; Blindness; Collection; Complex; Condition; Development; Dimethyl Sulfoxide; Drug Kinetics; Ensure; Evaluation; Fluorescence; Genomics; Goals; Human; Hybrids; Legal Blindness; Luciferases; Maintenance; Mus; Nonexudative age-related macular degeneration; Nuclear Orphan Receptor; Patients; Photoreceptors; Play; Point Mutation; Property; Regulation; Reporter; Retina; Retinal; Retinal Degeneration; Role; Screening procedure; Signal Transduction; Specificity; System; Testing; Time; Transactivation; United States National Institutes of Health; Variant; Vertebrate Photoreceptors; assay development; base; beta-Lactamase; concept; day; design; macula; photoreceptor degeneration; research study; small molecule; tool

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of legal blindness in the US. There is no effective treatment for the most prevalent atrophic (dry) form of AMD. The loss of vision in atrophic AMD is caused by degeneration of photoreceptor cells (rods and cones) in the central part of the retina called macula. Preservation of macular rods and cones is the ultimate goal of AMD treatment. NR2E3 is an orphan nuclear receptor expressed exclusively in photoreceptor cells of the retina where it is involved in photoreceptor maintenance and differentiation. Our overall objective is to identify a small molecule NR2E3 agonist suitable for performing proof-of-concept photoreceptor protection experiments in animal models of retinal degeneration. Identification of NR2E3 agonists will also provide an important pharmacological tool for probing basic biologic mechanisms of photoreceptor development and differentiation. The studies outlined in this proposal seek to develop an HTRF assay for agonist-induced release of corepressor NCOR from the NR2E3-NCOR complex (Specific Aim 1) and to adapt this assay to the HTS format suitable for screening of a compound collection at one of the NIH MLSCN screening centers (Specific Aim 2).

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是美国法律失明的最常见原因。对于最普遍的萎缩（干）AMD，没有有效的治疗方法。萎缩性AMD中视力的丧失是由视网膜中央部分的光感受器细胞（棒和锥）变性引起的，称为黄斑。保存黄斑杆和锥是AMD处理的最终目标。 NR2E3是一种仅在视网膜的感光细胞中表达的孤儿核受体，其参与光感受器的维持和分化。我们的总体目标是确定一个小分子NR2E3激动剂，适合于视网膜变性动物模型中进行概念验证光感受器保护实验。 NR2E3激动剂的鉴定还将提供一个重要的药理学工具，用于探测感光器发育和分化的基本生物学机制。该提案中概述的研究旨在开发一种HTRF测定法，以通过NR2E3-NCOR复合物从NR2E3-NCOR复合物中释放corepressor ncor（特定目标1），并将此测定适应适用于HTS格式，适用于HTS格式，适用于在NIH MLSC NIH MLSCN筛选中筛选一个化合物集合（特定的AIM AIM 2）。