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

描述(申请人提供)：萎缩型(“干性”)的老年性黄斑变性(AMD)，这是最常见的形式的疾病，基本上是无法治疗的。越来越多的证据表明，视网膜色素上皮(RPE)细胞的功能障碍和丢失在AMD的病理生理过程中起重要作用。因此，已经做出努力，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，以取代功能失调和丢失的RPE细胞。在这项应用中，我们建议采用互补的高通量筛选(HCS)和高内容筛选(HCS)方法来识别促进氧化应激下的人干细胞来源的RPE细胞存活的小分子(特定目标1)和促进干细胞向RPE表型分化的分子(特定目标2)。鉴于氧化应激与AMD有关，目标1中确定的分子有望作为开发干性AMD治疗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基于细胞的干性AMD治疗方法。此外，来自这两个AIMS的分子也将作为分子探针，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。

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.