Molecular control of retinal stem cell development

视网膜干细胞发育的分子控制

• 批准号: 6870407
• 负责人: Peter H Mathers
• 金额: $ 32.85万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870407
• 关键词: cell differentiation; cell proliferation; developmental genetics; gene expression; genetically modified animals; growth /development; immunocytochemistry; in situ hybridization; laboratory mouse; optic disk; retina; retinal pigment epithelium; stem cells

DESCRIPTION (provided by applicant): Knowledge of the genetic and molecular mechanisms by which the fate of retinal stem cells is determined will be necessary to manipulate the proliferation and differentiation potential of these cells for use in regeneration therapies to treat retinal diseases. We are focused on understanding the genes that control early commitment to neural and pigmented retinal identity with the intention of manipulating these genes to promote regeneration in the mammalian retina and to direct differentiation of specific cell types. Our work with the Rx homeobox gene demonstrates multiple roles for this transcription factor, ranging from initiation of optic vesicle formation, to determining neural retinal identity, and finally, to controlling growth and differentiation of retinal stem cells. Our long-term goal is to understand how proliferation and differentiation of the mammalian retina are regulated. In pursuit of this goal, the objective of this application is to investigate the role of the Rx gene in controlling the ability of a retinal stem cell to proliferate and differentiate. The central hypothesis of this proposal is that the Rx gene is necessary for determining and maintaining neural retinal cell identity and that it does so by promoting the proliferation of retinal stem cells at multiple stages during retinal development. The current proposal aims to continue our work on the Rx gene to understand its genetic and biochemical activities in early retinal development. The proposed work is designed in two Specific Aims: 1) to determine if Rx is both necessary and sufficient to specify neural retinal cell identity, using mouse transgenic and conditional deletion models of Rx gene function; and 2) to determine the role of the Rx gene in maintaining neural retinal progenitor proliferation. In this aim, conditional deletion of the Rx gene will be used to uncover its function in the optic cup. Collectively, these studies will yield important information that is necessary to manipulate endogenous retinal stem cells toward proliferation and ultimate use in restoring sight to the visually impaired.

描述（由申请人提供）：对决定视网膜干细胞命运的遗传和分子机制的了解对于操纵这些细胞的增殖和分化潜力以用于治疗视网膜疾病的再生疗法是必要的。我们专注于了解控制早期承诺的神经和色素视网膜的身份与操纵这些基因的意图，以促进在哺乳动物视网膜再生和特定细胞类型的直接分化的基因。我们的工作与Rx同源框基因证明了这种转录因子的多种作用，从启动视泡形成，以确定神经视网膜的身份，最后，控制视网膜干细胞的生长和分化。 我们的长期目标是了解哺乳动物视网膜的增殖和分化是如何调节的。为了实现这一目标，本申请的目的是研究Rx基因在控制视网膜干细胞增殖和分化能力中的作用。该提议的中心假设是Rx基因对于确定和维持神经视网膜细胞身份是必需的，并且其通过在视网膜发育期间的多个阶段促进视网膜干细胞的增殖来实现。 目前的提案旨在继续我们对Rx基因的研究，以了解其在早期视网膜发育中的遗传和生化活动。拟议的工作设计在两个特定的目的：1）确定Rx是否是必要的和足够的，以指定神经视网膜细胞的身份，使用小鼠转基因和条件性缺失模型的Rx基因功能;和2）确定Rx基因在维持神经视网膜祖细胞增殖的作用。在这个目标中，Rx基因的条件性缺失将用于揭示其在视杯中的功能。 总的来说，这些研究将产生重要的信息，这是必要的操纵内源性视网膜干细胞增殖和最终用于恢复视力的视力受损。