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Signal Integration During Eye Formation

眼睛形成过程中的信号整合

基本信息

批准号：
10245151
负责人：
Nadean L Brown
金额：
$ 34.27万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245151
关键词：
Address Alleles Anophthalmos Apoptosis Binding Bioinformatics Biology Brain Cancer Biology Cell Maintenance Cell Polarity Cell Proliferation Cell membrane Cell surface Cells Cilia Coloboma Complex Confocal Microscopy Cre driver Data Development Diffuse Disease Embryo Embryology Enhancers Etiology Eye Eye Abnormalities Eye Development Generations Genes Genetic Goals Growth Histology Holoprosencephaly Hour Human Hypothalamic structure Immunohistochemistry Impairment In Situ Hybridization In Vitro Ligands Microphthalmos Molecular Morphogenesis National Eye Institute Neural Retina Neurons Optic Disk Optic Nerve Optic vesicle Organogenesis Organoids Outer Limiting Membrane Pathogenesis Pathway interactions Pattern Pituitary Gland Process Production Regulation Reporting Research Retina Retinal Cone Retinal Ganglion Cells Role SMO gene Septo-Optic Dysplasia Signal Pathway Signal Transduction Sonic Hedgehog Pathway Spinal Cord Subthalamic structure System Techniques Technology Testing Time Tissues Transgenic Mice Transgenic Organisms Untranslated RNA Visual base diencephalon experimental study eye formation gastrulation histogenesis in vivo induced pluripotent stem cell insight lens malformation morphogens mouse genetics mutant mutant mouse model neurogenesis notch protein optic cup optic stalk receptor receptor expression response retinal progenitor cell skin organogenesis smoothened signaling pathway spatiotemporal stem cell biology stem cell growth stem cells

项目摘要

Project Summary: A long-standing question in biology is how cells respond to multiple signaling inputs with a specific response. This proposal investigates the intersections of Notch and Hh signaling pathways, which are widely required during development, and basic mechanisms congenital eye disease. Both signaling systems regulate cell proliferation, morphogenesis, cell polarity, differentiation, apoptosis and stem cell maintenance. However, the spatiotemporal contexts for each differs at the cellular and tissue levels during optic vesicle morphogenesis and growth. This proposal will use in vivo complex conditional (cre-lox) mouse genetics, mouse transgenics, embryology, iPSC-derived retinal organoids, histology, immunohistochemistry, confocal microscopy, in situ hybridization, qPCR and bioinformatics technologies to investigate basic, mechanistic questions about the initiation and progression of eye formation from the embryonic brain. We will address several important questions: 1) What are the spatial and temporal constraints for Notch versus Hh in controlling growth, morphogenesis, patterning, tissue polarity and the timing of differentiation in the optic vesicle, optic cup, RPE and optic stalk? 3) What are the optimal conditions by which Notch and Shh pathways contribute to the generation of retinal ganglion cell and cone photoreceptor neurons in retinal organoid culture? 1) How do the Notch and Hh pathways regulate the eye expression domains of a common target gene, Hes1?

项目概要：生物学中一个长期存在的问题是细胞如何以特定的反应对多种信号输入做出反应。该提案调查了广泛需要的Notch和Hh信号通路的交叉点在发展过程中，和基本机制先天性眼病。这两个信号系统调节细胞增殖、形态发生、细胞极性、分化、凋亡和干细胞维持。然而，在视泡形态发生过程中，每一种的时空背景在细胞和组织水平上不同和生长。该提案将使用体内复杂条件性（cre-β lox）小鼠遗传学、小鼠转基因，胚胎学，iPSC-GFP衍生的视网膜类器官，组织学，免疫组织化学，共聚焦显微镜，原位杂交，qPCR和生物信息学技术，以调查有关的基本，机制问题，眼形成的起始和进展从胚胎脑。我们将解决几个重要的问题：1）Notch与Hh在控制增长方面的空间和时间限制是什么，视泡、视杯、RPE中的形态发生、图案化、组织极性和分化时间和视柄 3)Notch和Shh通路促进细胞凋亡的最佳条件是什么？视网膜类器官培养中视网膜神经节细胞和视锥感光神经元的产生？ 1)是如何 Notch和Hh途径调节一个共同的靶基因，Hes 1？