NEW NEURONS IN THE RETINA

描述(改编自申请人的摘要)：总体目标 这项研究是为了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。这个 从体内和体内研究的许多实验室积累的证据 体外实验和一些不同的脊椎动物物种表明 祖细胞的发育潜力，即其生产 特定的视网膜细胞类型，在视网膜过程中逐渐改变 发展。此建议集中在选定的子集 可能涉及到的分子相互作用 视网膜祖细胞中的细胞命运：细胞表面信号分子-- 黏附分子钙粘蛋白家族与Notch-Delta信号转导 途径和它调节的转录调节因子，以及成对的类 同源域蛋白已被牵连到控制 选定祖细胞类的增殖和测定。这个 研究人员建议研究R-钙粘附素的表达和功能， 确定哪些钙粘附素(S)在光感受器中表达，然后阻断其 抗体和反义抗体在视网膜发育中的作用 寡核苷酸和检测对片层和细胞的特异性影响 差异化。将对视网膜前体细胞进行调查 表达成对类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 决定基因和钙粘附素。然后调查员将测试 关于调控基因表达组合模式的假说 反映发展潜力，从多能干细胞到承诺 祖先。这一“视网膜生成”模型也将在视网膜上进行测试。 在金鱼身上发展的再生试验，现在建议扩展到 斑马鱼。这里概述的研究旨在揭示机制 参与视网膜细胞的测定和分化，以及 视网膜细胞的再生替换，可能提供对 受损的人类视网膜组织的替代疗法。

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.