Role of Chx10 in embryonic Retinal Progenitor Cells

Chx10 在胚胎视网膜祖细胞中的作用

基本信息

批准号：
7581561
负责人：
EDWARD M LEVINE
金额：
$ 37.63万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7581561
关键词：
Address Adult Agonist Alleles Animals Anophthalmos Automobile Driving Biological Assay Birth Breeding Cell Cycle Progression Cell Differentiation process Cell Proliferation Cells Characteristics Child Complex Critical Pathways Defect Dependence Development Embryo Environment Erinaceidae Eye Eye Development Failure Gene Expression Genes Genetic Goals Homeobox Genes Human Knock-out Laboratories Ligands Maps Measurement Mediating Membrane Methods Microphthalmos Mitogens Molecular Mus Mutation Nature Neonatal Neural Retina Optic vesicle Optics Pathway interactions Pattern Phenotype Preparation Property Proteins Reporting Research Retina Retinal Retinal Diseases Role Series Signal Pathway Signal Transduction Staging Stem cells Tamoxifen Time Visual impairment Work base blind disability extracellular eye formation homeodomain human SMO protein insight malformation neuroepithelium neurogenesis null mutation optic cup programs public health relevance recombinase research study restorative treatment retinal progenitor cell smoothened signaling pathway transcription factor

项目摘要

DESCRIPTION (provided by applicant): The homeodomain-containing transcription factor Chx10 is a central regulator of retinal development. Much of what we know about Chx10 function comes from studies using ocular retardation J (orJ) mice, which have a null mutation in the Chx10 gene. Work from our laboratory has contributed to an understanding of its role in retinal progenitor cell (RPC) proliferation and cell cycle progression. Additionally, our work and others reveal that Chx10 also influences the timing of neurogenesis, maintains neuroretinal identity, regulates adult retinal stem cells, and is required for bipolar cell formation. The primary goal of our work is to uncover the specific Chx10-dependent molecular mechanisms and pathways driving retinal development. One challenge in achieving this goal is that multiple alterations in RPC properties (assessed in orJ mice) overlap in time and initiate early in retinal development. Because of this, it is not known if these changes are mediated by shared mechanisms and whether Chx10 is required for regulating RPC properties at later stages of development. To resolve these issues and gain insight into molecular mechanisms of Chx10 function, we propose three aims. In Aim 1, we will perform a series of genetic experiments using a conditional allele of Chx10 and chimeric mice to determine developmental stages when Chx10 required in RPCs and to determine if RPC changes induced by Chx10 loss are due solely to cell-autonomous mechanisms. In Aims 2 and 3, we investigate two potential mechanisms of Chx10 function. Aim 2 builds on our recent study of hedgehog signaling indicating that loss of Chx10 influences the efficiency of signaling pathways important for proliferation. Using culture assays and gene expression measurements, we will investigate how Chx10 interacts with the hedgehog pathway. In Aim 3, we investigate a potential interaction between Chx10 and the homeodomain-containing transcription factor Lhx2 (an essential regulator of early eye development) using genetic approaches in mice. Our studies have the potential to provide a rich map of the complex mechanisms controlling formation of the retina and could provide insights into the refined use of stem cells for treating retinal disease. PUBLIC HEALTH RELEVANCE: Microphthalmia is a congenital anomaly in which the eye fails to grow to its normal size. Ocular malformations, which include microphthalmia are reported to be as high as 1 in 5000 births and children born with these malformations are often severely visually impaired or blind. The goals of the research proposed here are to understand the basis for these defects with the hope of one day developing a restorative treatment or cure for these devastating disabilities.

描述（由申请人提供）：含有同源结构域的转录因子 Chx10 是视网膜发育的中央调节因子。我们对 Chx10 功能的了解大部分来自于对眼部发育迟缓 J (orJ) 小鼠的研究，这些小鼠的 Chx10 基因存在无效突变。我们实验室的工作有助于了解其在视网膜祖细胞 (RPC) 增殖和细胞周期进展中的作用。此外，我们和其他人的工作表明，Chx10 还影响神经发生的时间、维持神经视网膜特性、调节成体视网膜干细胞，并且是双极细胞形成所必需的。我们工作的主要目标是揭示驱动视网膜发育的特定 Chx10 依赖性分子机制和途径。实现这一目标的一个挑战是 RPC 特性的多种改变（在 orJ 小鼠中评估）在时间上重叠并在视网膜发育早期启动。因此，尚不清楚这些变化是否是由共享机制介导的，以及在开发的后期阶段是否需要 Chx10 来调节 RPC 属性。为了解决这些问题并深入了解 Chx10 功能的分子机制，我们提出了三个目标。在目标 1 中，我们将使用 Chx10 的条件等位基因和嵌合小鼠进行一系列遗传实验，以确定 RPC 需要 Chx10 时的发育阶段，并确定 Chx10 丢失引起的 RPC 变化是否仅归因于细胞自主机制。在目标 2 和 3 中，我们研究了 Chx10 功能的两种潜在机制。目标 2 建立在我们最近对刺猬信号传导的研究之上，该研究表明 Chx10 的丢失会影响对增殖至关重要的信号传导途径的效率。通过培养测定和基因表达测量，我们将研究 Chx10 如何与刺猬通路相互作用。在目标 3 中，我们利用小鼠遗传方法研究了 Chx10 与含有同源结构域的转录因子 Lhx2（早期眼睛发育的重要调节因子）之间的潜在相互作用。我们的研究有可能提供控制视网膜形成的复杂机制的丰富图谱，并可以为干细胞治疗视网膜疾病的精细使用提供见解。公众健康相关性：小眼症是一种先天性异常，眼睛无法长到正常大小。据报道，包括小眼球在内的眼部畸形的发生率高达五千分之一，患有这些畸形的儿童通常会严重视力受损或失明。这里提出的研究的目标是了解这些缺陷的基础，希望有一天能够开发出一种恢复性治疗或治愈这些毁灭性残疾的方法。