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

描述（由申请人提供）：年龄相关性黄斑变性（AMD）的萎缩（“干性”）形式是该疾病的最常见形式，在很大程度上是不可治疗的。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的病理生理中起着重要作用。因此，已经努力A）开发促进RPE健康和存活的试剂，和B）开发基于细胞移植的方法来替换功能障碍和丢失的RPE细胞。在本申请中，我们提出采用互补的高容量筛选（HCS）和高含量筛选（HCS）方法来鉴定促进暴露于氧化应激的人干细胞衍生的RPE细胞的存活的小分子（特异性目标1）和促进干细胞向RPE表型分化的分子（特异性目标2）。考虑到氧化应激与AMD有关，目标1中鉴定的分子将有望作为开发干性AMD治疗的细胞保护方法的先导分子。目标2中鉴定的分子将有望有助于开发基于细胞的干性AMD治疗方法。此外，来自两个目标的分子也将用作分子探针，其将用于研究决定RPE分化和调节RPE细胞对氧化应激的反应的机制。

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.