Investigation of Mammalian Retinal Neuron Development

哺乳动物视网膜神经元发育的研究

• 批准号: 8427626
• 负责人: Nadean L Brown
• 金额: $ 23.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427626
• 关键词: Investigation; Mammalian; Retinal; Neuron; Development

Abstract This proposal investigates the underlying causes of human ocular diseases using mouse models. We focus on the Notch signaling pathway, which is critically required in multiple mammalian tissues. In particular, Notch signaling regulates proliferation, apoptosis, cell shape changes, differentiation and stem cell maintenance. Experiments in this proposal will 1) elucidate the epistatic relationship between Notch signaling and Math5 during retinal ganglion cell (RGC) neurogenesis 2) explore the multiple retinal neuron phenotypes of Rbpj, and 3) define the requirements of the Notch ligand Deltalike1 during retinal neurogenesis. Because Notch signaling is widely employed during development, mouse mutations in most Notch pathway genes have already been created. Using targeted deletion mice (wholly mutant and conditional alleles), we propose to understand the requirements for canonical Notch signaling during retinal ganglion cell and cone and rod photoreceptor formation. Some studies will employ conditional (cre-lox) mouse strains, histology, immunohistochemistry, in situ hybridization, mouse embryology and PCR genotyping. Others will test regulatory relationships in vitro using a human retinoblast cell line and biochemical assays. These studies will contribute fundamental information retinal progenitor cell growth, morphogenesis and differentiation, which occur throughout all metazoan development. This work will yield a better understanding of cone-rod dystrophies, optic nerve aplasia, hypoplasia, as well as contribute to basic mechanisms of retinal cell development with direct relevance to gene- or cell-based retinal therapies. Findings here will also be widely useful to the pathologies of CADASIL and Alagille Syndromes, and cancer biology, since abnormal expression of Notch pathway genes occurs in each of these diseases.

抽象的 该提案研究了使用小鼠的人眼疾病的根本原因 型号。我们专注于Notch信号通路，这在多个中至关重要 哺乳动物组织。特别是，Notch信号传导调节增殖，凋亡，细胞 形状变化，分化和干细胞维护。该提案中的实验 1）阐明Notch信号传导与MATH5之间的上皮关系 视网膜神经节细胞（RGC）神经发生2）探索多个视网膜神经元 RBPJ的表型和3）定义了Notch配体deltalike1的要求 视网膜神经发生。由于Notch信号在开发过程中广泛使用，因此 大多数Notch途径基因中的小鼠突变已经创建。使用 有针对性的缺失小鼠（完全突变和条件等位基因），我们建议理解 视网膜神经节细胞和锥体期间的规范凹槽信号传导的要求 杆光感受器的形成。一些研究将采用条件（Cre-lox）小鼠 菌株，组织学，免疫组织化学，原位杂交，小鼠胚胎学和 PCR基因分型。其他人将使用人类在体外测试监管关系 视网膜细胞系和生化测定。这些研究将有助于基本 信息视网膜祖细胞的生长，形态发生和分化，发生 在所有后生发展中。这项工作将更好地理解 锥体杆营养不良，视神经发育不全，发育不全，并有助于碱性 视网膜细胞发育的机制与基因或基于细胞的直接相关 视网膜疗法。这里的发现也将对卡达西的病理有用 由于缺口异常表达，阿拉吉综合征和癌症生物学 途径基因发生在每种疾病中。