AMD THERAPY: A Screen for Molecules that Promote RPE Survival and Differentiation

AMD 疗法：促进 RPE 存活和分化的分子筛选

• 批准号: 8575156
• 负责人: Donald J. Zack
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575156
• 关键词: Adherent Culture; Age related macular degeneration; Apoptotic; Atrophic; Autologous; Automobile Driving; Biological Assay; Biology; Blindness; Cell Survival; Cell Transplantation; Cells; Cessation of life; Cytoprotection; Data; Development; Disease; Elderly; Epithelial; Functional disorder; Health; Human; Injury; Lead; Length; Measures; Mediating; Molecular Probes; Monophenol Monooxygenase; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Photoreceptors; Play; Pluripotent Stem Cells; Process; Research Personnel; Residual state; Retinal Pigments; Role; Source; Stem cells; Stress; Structure of retinal pigment epithelium; Technology; Testing; Therapeutic; Transplantation; Vision; Western World; Work; base; bevacizumab; fetal; fetus cell; high throughput screening; human embryonic stem cell; human stem cells; improved; insight; neovascular; novel; novel therapeutics; oxidation; oxidative damage; promoter; public health relevance; response; screening; small molecule; small molecule libraries; stem; stem cell differentiation; tool; treatment strategy

DESCRIPTION (provided by applicant): The atrophic ("dry") form of age-related macular degeneration (AMD), which is the most common form of the disease, is largely untreatable. Accumulating evidence suggests that dysfunction and loss of retinal pigment epithelial (RPE) cells plays an important role in the pathophysiology of AMD. Efforts have therefore been made to A) develop agents that promote RPE health and survival and B) develop cell transplantation-based approaches to replace the dysfunctional and lost RPE cells. In this application we propose to take complementary High Throughput Screening (HCS) and High Content Screening (HCS) approaches to identify small molecules that promote the survival of human stem cell-derived RPE cells exposed to oxidative stress (Specific Aim 1) and molecules that promote the differentiation of stem cells towards an RPE phenotype (Specific Aim 2). Given that oxidative stress has been implicated in AMD, the molecules identified in Aim 1 will hopefully serve as lead molecules for the development of cytoprotective approaches for dry AMD therapy. And the molecules identified in Aim 2 will hopefully aid in the development of improved cell-based treatment approaches for dry AMD. In addition, the molecules from both aims will also serve as molecular probes that will be useful in study of the mechanisms that determine RPE differentiation and that modulate the RPE cell's response to oxidative stress.

描述（由申请人提供）：萎缩性（“干性”）形式的年龄相关性黄斑变性（AMD）是该疾病最常见的形式，在很大程度上是无法治疗的。越来越多的证据表明，视网膜色素上皮 (RPE) 细胞的功能障碍和丧失在 AMD 的病理生理学中起着重要作用。因此，人们努力 A) 开发促进 RPE 健康和存活的药物，B) 开发基于细胞移植的方法来替代功能失调和丢失的 RPE 细胞。在此应用中，我们建议采用互补的高通量筛选 (HCS) 和高内涵筛选 (HCS) 方法来识别促进暴露于氧化应激的人类干细胞衍生的 RPE 细胞存活的小分子（具体目标 1）以及促进干细胞向 RPE 表型分化（具体目标 2）。鉴于氧化应激与 AMD 相关，Aim 1 中鉴定的分子有望成为开发干性 AMD 疗法的细胞保护方法的先导分子。 Aim 2 中确定的分子有望有助于开发改进的干性 AMD 细胞治疗方法。此外，这两个目标的分子也将用作分子探针，可用于研究决定 RPE 分化和调节 RPE 细胞对氧化应激反应的机制。