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Gene regulation of retinal cell differentiation

视网膜细胞分化的基因调控

基本信息

批准号：
10478103
负责人：
WEI LIU
金额：
$ 40.74万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478103
关键词：
Adult Affect Amacrine Cells Award Biology Blindness Cell Differentiation process Cell Proliferation Cells Ciliary Body DNA Binding Development Developmental Process FZD1 gene Fibroblast Growth Factor Funding Gene Expression Regulation Genes Genetic Goals Human Individual Iris Knowledge Laboratories Ligands Maintenance Modeling Molecular Morphogenesis Mus Natural regeneration Pathway interactions Pattern Peripheral Phenotype Population Proteins Regenerative Medicine Regulation Research Retina Retinal Degeneration Role Signal Transduction Signal Transduction Pathway Specific qualifier value Stratification Structure of retinal pigment epithelium System Testing Therapeutic Tissues Transforming Growth Factor beta Vision beta catenin cis acting element differential expression epithelial stem cell genetic corepressor insight mouse model multipotent cell optic cup overexpression paralogous gene postnatal progenitor programs rational design receptor regenerative therapy retinal damage retinal neuron single-cell RNA sequencing stem cells transcription factor transcriptome sequencing

项目摘要

Abstract The long-term goal of this research program is to elucidate the fundamental mechanisms underlying mammalian retinal development through molecularly dissecting the roles of transcription factors and signal transduction molecules. In the adult retina, the neuroretina, retinal pigment epithelium, ciliary body, and iris are structurally connected to execute visual functions. During development, the progenitor cells that give rise to these adult retinal tissues are closely related. Morphogenesis of optic cups results in the specification and regionalization of neuroretinal and retinal pigment epithelial progenitor cells in the inner and outer layers of optic cups, respectively. Subsequently, ciliary margin progenitor cells are specified at the periphery of the neuroretina, contributing to the ciliary body and iris. Neuroretinal progenitor cells are multipotent; their coordinated cell proliferation and differentiation produce stratified neuroretina. Abnormalities in any of developmental processes result in retinal blindness. In retinal development, cell specification, cell identity maintenance, and differentiation are tightly regulated by transcription factors, including Six3, Six6, Pax6, Rax, Sox2, and Lhx2. Signaling transduction pathways, including Wnt, FGF, HH, BMP, and TGFβ, interplay with the transcription factors. How multipotent neuroretinal progenitor cells are regulated, and how the maintenance of neuroretinal progenitor cells and the specification of ciliary margin progenitors are coordinated along the peripheral-central axis are still critical knowledge gaps. In the previous funding period, we have demonstrated that Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitor cells in mice. We hypothesize that Six3 and Six6 directly regulate multiple major targets to maintain the identity of multipotent neuroretinal progenitor cells. The hypothesis will be tested using both candidate and unbiased approaches. We will first determine the major targets of Six3 and Six6 in suppressing Wnt/β-catenin signaling to maintain multipotent neuroretinal cell identity (Aim 1), and then elucidate the molecular mechanisms by which Six3 and Six6 jointly suppress ciliary margin cell fate at the far periphery but maintain the multipotency of neuroretinal progenitor cells at the mid periphery in the neuroretina (Aim 2). The proposed studies are built upon our intriguing mouse models as well as unbiased cutting-edge approaches already established in our laboratory. When completed, these studies will provide deeper insights into the molecular and cellular mechanisms of retinal differentiation and uncover therapeutic opportunities for regenerative medicine of the human neuroretina. 1

摘要这项研究计划的长期目标是阐明哺乳动物视网膜发育通过分子解剖转录因子和信号的作用转导分子在成人视网膜中，神经视网膜、视网膜色素上皮、睫状体和虹膜在结构上相互连接以执行视觉功能。在发育过程中，与这些成人视网膜组织密切相关。视杯的形态发生导致质量标准以及神经视网膜和视网膜色素上皮祖细胞在内和外的区域化视杯层。随后，睫状缘祖细胞被指定在周边神经视网膜的一部分，对睫状体和虹膜起作用。神经视网膜祖细胞是多能的;它们的协调的细胞增殖和分化产生分层的神经视网膜。在任何一个发育过程导致视网膜失明。在视网膜的发育，细胞的规格，细胞的身份维持和分化受到转录因子的严格调控，包括Six 3，Six 6，Pax 6， Rax、Sox 2和Lhx 2。信号转导途径，包括Wnt、FGF、HH、BMP和TGFβ，与转录因子的关系。多能神经视网膜祖细胞是如何被调节的，神经视网膜祖细胞的维持和睫状缘祖细胞的特化是沿着外围-中心轴线协调，仍然存在严重的知识差距。在此前的融资中，期间，我们已经证明，Six 3和Six 6是共同需要的多能维持神经视网膜前体细胞。我们假设Six 3和Six 6直接调节多种主要的靶点以维持多能神经视网膜祖细胞的身份。假设将被检验使用候选和无偏的方法。我们将首先确定Six 3和Six 6的主要目标，抑制Wnt/β-catenin信号传导以维持多能神经视网膜细胞身份（Aim 1），然后阐明Six 3和Six 6联合抑制睫状缘细胞命运的分子机制，但在中周边维持神经视网膜祖细胞的多能性。神经视网膜（Aim 2）。拟议的研究是建立在我们有趣的小鼠模型以及公正的我们实验室已经建立的尖端方法。完成后，这些研究将提供更深入地了解视网膜分化的分子和细胞机制，人类神经视网膜再生医学的机会。 1