The molecular basis of planarian regeneration

我们的目标是识别基因和遗传途径并对其进行功能表征 支撑后生动物的再生。我们建议使用涡虫 Schmidtea 地中海作为解决这个问题的模型系统，因为它是 最简单的头侧对称动物，具有复杂的器官系统，显示出广泛的 再生能力：被斩首的动物能够再生并在功能上整合 一周内将新的头部移植到先前存在的组织上。此外，如此引人注目的 发育可塑性是由丰富且可通过实验获得的 称为新生细胞的全能干细胞群。期间取得的进展 最后一段资金用于询问基因功能和测量再生反应， 结合地中海沙门氏菌基因组的测序和最新注释 创造了前所未有的机会来解决动物再生问题 分子和功能基因组术语。我们建议充分利用 涡虫提供的吞吐能力和生物可塑性，以建立 再生的详细分子景观。我们建议：1）进行基因组- 使用高密度 DNA 阵列对再生进行广泛、高时间分辨率的分析； 2）测试关键的、进化上保守的胚胎信号通路的功能 组织稳态和再生的成人背景提供功能基础 用于解释微阵列实验； 3）进行器官特异性筛选 再生以确定分子专业化的调控范围和程度 存在于一般的再生事件中。综合起来，这些研究应该为我们提供 迄今为止进行了最全面的再生机制研究，并且 应作为正式测试进化分歧或趋同的平台 动物的再生是阻碍再生的一个未解决的核心问题 对再生能力较差的患者实施合理的再生治疗，例如 哺乳动物。

Our objective is to identify and functionally characterize the genes and genetic pathways underpinning metazoan regeneration. We propose to use the planarian Schmidtea mediterranea as a model system to address this problem because it is among the simplest cephalized bilaterians with complex organ systems that display extensive regenerative capacities: a decapitated animal will regenerate and functionally integrate a new head to the pre-existing tissues in under a week. In addition, such remarkable developmental plasticity is driven by an abundant and experimentally accessible population of totipotent stem cells known as neoblasts. The advances made during the last period of funding to interrogate gene function and measure regenerative responses, combined with the sequencing and recent annotation of the S. mediterranea genome create an unprecedented opportunity to frame the problem of animal regeneration in molecular and functional genomic terms. We propose to take full advantage of the throughput capacity and biological plasticity afforded by planarians to establish a detailed molecular landscape of regeneration. We propose to: 1) carry out genome- wide, high temporal resolution analyses of regeneration using high density DNA arrays; 2) test the functions of key, evolutionarily conserved embryonic signaling pathways in the adult contexts of tissue homeostasis and regeneration to provide a functional basis for interpreting the microarray experiments; and 3) to carry out screens of organ-specific regeneration to determine the regulatory extent and degree of molecular specialization that exists in general regenerative events. Combined, these studies should provide us with the most comprehensive mechanistic study of regeneration performed to date, and should serve as a platform to formally test the evolutionary divergence or convergence of regeneration among animals, a central unresolved aspect hindering the implementation of rational regenerative therapeutics in poor regenerators such as mammals.