Molecular control of retinal stem cell development

描述（由申请人提供）：掌握决定视网膜干细胞命运的遗传和分子机制对于操纵这些细胞的增殖和分化潜力用于视网膜疾病的再生疗法是必要的。我们专注于了解控制神经和色素视网膜身份的早期承诺的基因，目的是操纵这些基因来促进哺乳动物视网膜的再生和指导特定细胞类型的分化。我们对Rx同源盒基因的研究表明，该转录因子具有多种作用，从启动视神经囊泡形成，到决定神经视网膜身份，最后控制视网膜干细胞的生长和分化。

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.