Mechanisms of Hydra Development and Regeneration

项目摘要/摘要 在再生动物中，成年动物的灾难性损伤，如失去肢体，会激活发育 生长出新的身体部位的途径。相比之下，灾难性的损伤会导致瘢痕形成和功能丧失 人类。无论动物的再生能力如何，对损伤的分子反应都是保守的，所以 一个关键的悬而未决的问题是理解为什么伤害反应激活了一些 动物，而不是其他动物。我们的长期目标是回答这个问题，这要求我们破译 损伤诱导转录因子与发育程序的调控关系 再生性动物。这应该通过细胞分辨率来完成，因为细胞类型对 并在再生过程中扮演不同的角色。为了实现我们的目标，我们研究了简单的蛇形动物 因为成虫表现出持续活跃的动态平衡发育和再生能力 对灾难性伤害的反应；这使我们能够解剖体内平衡和再生 并行发展，将两者直接比较和联系起来。因此，我们的实验室 有两个主要的研究方向：1)阐明驱动驱动的信号通路和转录网络 动态平衡发育和2)确定伤害信号如何触发这些发育程序 再生。为了了解内环境平衡的发育，我们使用单细胞rna-seq(scrna-seq)捕获所有 成体的细胞状态，包括分化过程中的细胞。我们将细胞置于发育中 确定在关键发育决策点表达的转录因子的轨迹，我们将对其进行测试 通过功能实验。此外，我们还将在信号通路之后重复scrna-seq实验。 扰动以确定这些通路如何控制动态平衡动物的细胞类型规格。至 为了了解再生发育，我们已经识别了损伤诱导的转录因子及其可能的 监管目标。我们将测试这些转录因子的功能，目的是使 伤害反应和发育计划之间的联系。此外，我们还将进行scRNA-seq 以及再生时间进程上的轨迹分析，以获得对单元规格的全局理解 再生发育过程中发生的事件。我们的研究计划将提高对基本知识的理解 发育生物学过程，这将对人类健康产生积极影响，因为：1)错误 细胞类型规范最终导致疾病，因此了解正常发育是如何发生的 我们对疾病的理解，2)在治疗医学的培养皿中实现干细胞分化依赖于 关于在发育模型系统中关于细胞规格的基本发现，以帮助指导 实验，以及3)了解损伤和发育之间的联系是如何发生在一些动物身上的， 但不是其他的，是利用这种力量造福于治疗药物的关键。

PROJECT SUMMARY/ABSTRACT In regenerative animals, catastrophic injury in the adult, such as loss of a limb, activates developmental pathways to grow a new body part. In contrast, catastrophic injuries lead to scarring and loss of function in humans. The molecular response to injury is conserved in animals regardless of their regenerative abilities, so a critical open question is to understand why the injury response activates developmental pathways in some animals, but not others. Our long-term goal is to answer this question, which requires that we decipher the regulatory connections between injury-induced transcription factors and developmental programs in regenerative animals. This should be done with cellular resolution because cell types respond differently to injury and have different roles during regeneration. To achieve our goals, we study the simple cnidarian Hydra vulgaris because the adult displays both continually active homeostatic development and regenerative development in response to catastrophic injury; this allows us to dissect both homeostatic and regenerative development in parallel and make direct comparisons and connections between the two. Thus our laboratory has two major research directions: 1) Elucidating the signaling pathways and transcriptional networks that drive homeostatic development and 2) Determining how injury signals trigger these developmental programs during regeneration. To understand homeostatic development, we use single-cell RNA-seq (scRNA-seq) to capture all cell states in the adult, including cells in the process of differentiation. We place cells into developmental trajectories to identify transcription factors expressed at key developmental decision points, which we will test with functional experiments. In addition, we will repeat scRNA-seq experiments after signaling pathway perturbations to determine how these pathways control cell type specification in a homeostatic animal. To understand regenerative development, we have identified injury-induced transcription factors and their putative regulatory targets. We will test the function of these transcription factors with the aim of making regulatory connections between the injury response and developmental programs. In addition, we will perform scRNA-seq and trajectory analysis over a regeneration time course to obtain a global understanding of cell specification events during regenerative development. Our research program will improve understanding of fundamental developmental biology processes and this will have a positive impact on human health because: 1) Errors in cell type specification ultimately lead to disease, thus understanding how normal development occurs informs our understanding of disease, 2) Engineering stem cell differentiation in a dish for therapeutic medicine relies on fundamental discoveries about cell specification made in developmental model systems to help guide experimentation, and 3) Understanding how the link between injury and development occurs in some animals, but not others, is a key to harnessing this power for the benefit of therapeutic medicine.