Molecular control of retinal stem cell development

描述(由申请人提供)：了解决定视网膜干细胞命运的遗传和分子机制，对于控制这些细胞的增殖和分化潜力，用于再生疗法治疗视网膜疾病是必要的。我们专注于了解控制神经和色素视网膜特性的早期承诺的基因，目的是操纵这些基因来促进哺乳动物视网膜的再生，并指导特定细胞类型的分化。我们对Rx Homeobox基因的研究显示了这种转录因子的多种作用，从启动视泡形成，到确定神经视网膜的特性，最后到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控的。为了实现这一目标，本应用的目的是研究Rx基因在控制视网膜干细胞增殖和分化能力中的作用。这一建议的中心假设是，Rx基因对于确定和维持神经视网膜细胞的特性是必要的，并且它通过在视网膜发育的多个阶段促进视网膜干细胞的增殖来实现这一点。 目前的建议旨在继续我们对Rx基因的研究，以了解其在视网膜早期发育中的遗传和生化活动。这项拟议的工作有两个特定的目的：1)利用小鼠转基因和Rx基因功能的条件删除模型，确定Rx是否是指定神经视网膜细胞身份的必要条件和充分条件；以及2)确定Rx基因在维持神经视网膜前体细胞增殖中的作用。为了达到这个目的，有条件地删除Rx基因将被用来揭示它在视杯中的功能。 总而言之，这些研究将产生重要的信息，这些信息对于控制内源性视网膜干细胞的增殖和最终用于恢复视力受损的人是必要的。

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.