NEW NEURONS IN THE RETINA

描述（改编自申请人摘要）：总体目标 这项研究旨在了解细胞间相互作用的分子基础 在发育和再生过程中调节视网膜神经发生。 的 从许多实验室积累的证据，无论是在体内， 体外和一些不同的脊椎动物物种表明， 祖细胞的发育潜力，即其产生 特定的视网膜细胞类型，在视网膜发育过程中逐渐改变， 发展 本建议集中于一个选定的子集， 分子间的相互作用，可能涉及到的决定， 视网膜祖细胞的细胞命运：细胞表面信号分子-- 粘附分子的钙粘蛋白家族和Notch-Delta信号传导 途径和它调节的转录调节因子，以及配对样 同源结构域蛋白质，已牵连在控制 增殖和确定选择的祖细胞类别。 的 研究者建议检测R-钙粘蛋白的表达和功能， 鉴定哪些钙粘蛋白在光感受器中表达，然后阻断它们的 在发育中的视网膜中的功能， 寡核苷酸，并检查对层压和细胞的特定影响 分化 视网膜祖细胞将被调查， 表达配对样分子的选定组合的亚群 在Notch通路中，包括它们的下游靶点，神经 决定基因和钙粘蛋白。 然后，研究人员将测试 调控基因表达组合模式假说 从多能干细胞到定向干细胞， 祖先 这种“视网膜生成”模型也将在视网膜中进行测试。 在金鱼中开发的再生试验，现在建议扩展到 斑马鱼 这里概述的研究旨在揭示 参与视网膜细胞的决定和分化， 视网膜细胞的再生替代，可以提供对 替代疗法用于受损的人类视网膜组织。

DESCRIPTION (Adapted from applicant's abstract): The overall objective of this research is to understand the molecular basis of cell-cell interactions that regulate retinal neurogenesis during development and regeneration. The accumulated evidence from many laboratories working both in vivo and in vitro and with a number of different vertebrate species suggests that the developmental potential of a progenitor cell, i.e. its ability to produce specific retinal cell types, is progressively altered during retinal development. This proposal concentrates on a selected subset of the molecular interactions that are likely to be involved in determination of cell fate in retinal progenitor cells: cell surface signaling molecules -- the cadherin family of adhesion molecules and the Notch-Delta signaling pathway and the transcriptional regulators it modulates, and the paired-like homeodomain proteins that have been implicated in the control of proliferation and determination of selected progenitor classes. The investigator proposes to examine the expression and function of R-cadherin, identify which cadherin(s) are expressed in photoreceptors, then block their function in the developing retina with antibodies and antisense oligonucleotides and examine specific effects on lamination and cell differentiation. Retinal progenitor cells will be surveyed for subpopulations that express selected combinations of paired-like molecules in the Notch pathway including their downstream targets, neural determination genes, and cadherins. The investigator will then test the hypothesis that combinatorial patterns of expression of regulatory genes reflect developmental potential, from pluripotent stem cells to committed progenitors. This "retinopoiesis" model will also be tested in a retinal regeneration assay developed in goldfish and now proposed to extend to zebrafish. The studies outlined here, designed to uncover mechanisms involved in retinal cell determination and differentiation and the regenerative replacement of cells in the retina, may provide insights into replacement therapies for damaged human retinal tissue.