Mechanisms of Hydra Development and Regeneration

项目总结/摘要 在再生动物中，成年动物的灾难性损伤，如肢体丧失，激活了发育过程， 生长新身体部位的途径。相比之下，灾难性的损伤会导致疤痕和功能丧失， 人类动物对损伤的分子反应是保守的，不管它们的再生能力如何， 一个关键的开放性问题是理解为什么损伤反应会激活某些人的发育途径， 动物，但不是其他动物。我们的长期目标是回答这个问题，这需要我们破译 损伤诱导的转录因子和发育程序之间的调节联系 再生动物这应该用细胞分辨率来完成，因为细胞类型对 在再生过程中有不同的作用。为了实现我们的目标，我们研究简单的刺胞动物水螅 因为成虫表现出持续活跃的体内平衡发育和再生能力， 在应对灾难性损伤的发展;这使我们能够解剖稳态和再生 并将两者进行直接的比较和联系。我们的实验室 有两个主要的研究方向：1）阐明信号通路和转录网络，驱动 稳态发育和2）确定损伤信号如何触发这些发育程序， 再生为了了解稳态发育，我们使用单细胞RNA-seq（scRNA-seq）捕获所有 细胞在成体中的状态，包括细胞在分化过程中的状态。我们将细胞置于发育中， 轨迹，以确定转录因子表达的关键发展决策点，我们将测试 功能性实验。此外，我们将在信号通路后重复scRNA-seq实验。 干扰以确定这些途径如何控制稳态动物中的细胞类型特化。到 了解再生发展，我们已经确定了损伤诱导的转录因子和它们的假定的 监管目标。我们将测试这些转录因子的功能，目的是使调节 伤害反应和发展计划之间的联系。此外，我们将进行scRNA-seq 以及再生时间过程上的轨迹分析，以获得对电池规格的全面理解 在再生发展过程中。我们的研究计划将提高对基础知识的理解 这将对人类健康产生积极影响，因为：1） 细胞类型的规范最终导致疾病，从而了解如何正常发展发生通知 我们对疾病的理解，2）在治疗药物的培养皿中工程干细胞分化依赖于 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，和3）了解伤害和发展之间的联系如何发生在一些动物， 而不是其他人，是利用这种力量造福于治疗医学的关键。

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.