Comparative systems biology defines regulatory mechanisms in whole-body regeneration

项目摘要 全身再生（再生所有身体部位的能力）是生物学中最大的奥秘之一。 利用这一过程将是一个医学上的登月胜利，因为它将提供治疗策略， 使人类患者任何类型的缺失组织再生。为了理解和控制 再生，我们需要揭示再生计划的完整监管网络，并确定关键的 可能导致这个网络功能障碍的机制。在这里，我们建议使用新的功能基因组 分析工具（空间转录组学，ATAC-seq和单细胞转录组学）与高 通过基因扰动实验来研究两种独特的实验范式。在第一个范例中， 我们将比较两种进化上的表亲：淡水涡虫，它是一种永生的扁形虫， 在整个动物王国中无与伦比的再生能力，以及致病的扁形虫， 只有有限的再生能力。我们将揭示短期的关键监管组成部分， 伤口诱导的反应，这是必不可少的启动和维持再生。在第二种模式中， 我们将研究通过外科手术构建的嵌合体，以解开调节 再生，以管理与细胞增殖相关的不受控制的长期风险。 反复再生。总的来说，我们的研究将促进对基本生物学的理解， 再生医学的基础，并为激活再生提供有用的目标。

Project Summary Whole-body regeneration (the ability to regenerate all body parts) is one of the greatest mysteries in biology. Harnessing this process would be a medical moonshot triumph, as it would provide therapeutic strategies to enable regrowth of any type of missing tissues in human patients. In order to understand and control regeneration, we need to uncover the full regulatory network of the regeneration program, and identify critical mechanisms that may lead to the dysfunction of this network. Here, we propose to use new functional genomic analysis tools (Spatial Transcriptomics, ATAC-seq, and single-cell transcriptomics) coupled with high- throughput gene perturbation experiments to study two unique experimental paradigms. In the first paradigm, we will compare two evolutionary cousins: the freshwater planarian, which is an immortal flatworm with unparalleled regenerative ability throughout the animal kingdom, and the pathogenic flatworm schistosome, which only has limited regenerative ability. We will reveal the critical regulatory components of the short-term wound-induced response that are essential for launching and sustaining regeneration. In the second paradigm, we will study surgically constructed planarian chimeras to unravel the immunological pathways that regulate regeneration in order to manage the long-term risks of uncontrolled cell proliferation that is associated with repeated regeneration. Collectively, our study will advance the understanding of the fundamental biological basis of regenerative medicine and provide useful targets for activating regeneration.