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Retinal Progenitors for Vision Rescue

视网膜祖细胞挽救视力

基本信息

批准号：
8698754
负责人：
ANDREA S VICZIAN
金额：
$ 30.48万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698754
关键词：
Accounting Address Age Age related macular degeneration Animal Model Automobile Driving Calcium Cell Culture Techniques Cell Ontogeny Cell Therapy Cells Characteristics Cone Data Development Ectoderm Ectoderm Cell Eye FGF2 gene Fibroblast Growth Factor Future Gene Proteins Generations Human Image In Vitro Lead Light Logic Molecular Mus Nuclear Translocation Pathway interactions Photoreceptors Phototransduction Physiological Play Property Relative (related person)Replacement Therapy Repression Research Retina Retinal Retinal Cone Retinal Degeneration Reverse Transcriptase Polymerase Chain Reaction Role SW opsin Signal Pathway Signal Transduction Source Staging Stem cells System Testing Time Transcript Transplantation Vision Vision research Visual system structure Work Xenopus base cell type design efficacy testing embryonic stem cell gene repression in vivo mouse model novel novel therapeutics patch clamp prenatal progenitor relating to nervous system research study response retinal damage retinal progenitor cell retinal rods therapy design vision development

项目摘要

DESCRIPTION (provided by applicant): Cone photoreceptors are the primarily cell class lost in Age-Related Macular Degeneration. Therapies designed to replace lost cones will require a rich source of these unique cells. Consequently, there is a clear need to identify the molecular mechanisms required to direct more plentiful pluripotent cells types to a cone lineage. We have developed a unique approach to addressing this problem. Our results demonstrate that mouse embryonic stem cells, first converted to primitive ectoderm, can be directed to a cone cell fate in culture. In vitro cone formation requires simultaneous repression of BMP and activation of FGF signaling, respectively. During neural induction, these two signaling pathways regulate SMAD1/5/8 nuclear translocation (BMP) and degradation (FGF), which directs ectodermal cells to a neural fate. In this application, we outline experiments designed to identify how these signaling pathways and their downstream components generate cone photoreceptor fate, by regulating both canonical and non-canonical BMP signaling as well as FGF signaling. Our hypothesis is that modulation of SMAD1/5/8 stability is required for cone formation. Previous studies have clearly demonstrated the developmental stage at which rod progenitors are transplanted to the host retina is critical for successful differentiation and integration of the cells. Our preliminary data demonstrates cone specific proteins and genes of the phototransduction cascade are already expressed in our cells. Characterizing their molecular, morphological and physiological properties will help us to determine the relative age of these in vitro-generated cones. Our research fits well into the National Plan for Eye and Vision Research objectives (http://www.nei.nih.gov/strategicplanning/ np_strab.asp), which include "determine(ing) how stem cells differentiate in the development of the visual system and how they can be used to understand the molecular logic of cell-type- specific identity in the visual system." This project will identify molecular mechanisms that contribute to cone cell generation and form the basis of future studies focusing on the ability of these cells to replace cones lost to retinal damage and degeneration.

描述（由申请人提供）：锥状光感受器是老年性黄斑变性的主要细胞类型。设计用于替换失去的视锥细胞的疗法将需要这些独特细胞的丰富来源。因此，有明确的需要，以确定所需的分子机制，引导更多的多能细胞类型到一个锥体谱系。我们开发了一种独特的方法来解决这个问题。我们的研究结果表明，首先转化为原始外胚层的小鼠胚胎干细胞可以在培养中定向为锥体细胞的命运。体外锥体的形成需要同时抑制BMP和激活FGF信号。在神经诱导过程中，这两条信号通路调节SMAD1/5/8核易位（BMP）和降解（FGF），从而指导外胚层细胞走向神经细胞的命运。在本应用中，我们概述了旨在确定这些信号通路及其下游成分如何通过调节规范和非规范BMP信号以及FGF信号来产生锥体光感受器命运的实验。我们的假设是SMAD1/5/8稳定性的调制是锥体形成所必需的。先前的研究已经清楚地表明，杆状祖细胞移植到宿主视网膜的发育阶段对细胞的成功分化和整合至关重要。我们的初步数据表明，锥特异性蛋白和光转导级联的基因已经在我们的细胞中表达。表征它们的分子、形态和生理特性将有助于我们确定这些体外生成的锥体的相对年龄。我们的研究非常符合国家眼与视觉研究计划的目标（http://www.nei.nih.gov/strategicplanning/ np_strab.asp），其中包括“确定干细胞如何在视觉系统的发展中分化，以及如何利用它们来理解视觉系统中细胞类型特异性身份的分子逻辑”。该项目将确定有助于视锥细胞生成的分子机制，并为未来研究这些细胞替代因视网膜损伤和变性而丢失的视锥细胞的能力奠定基础。