Mechanisms of Hydra Development and Regeneration

水螅发育和再生的机制

• 批准号: 10688063
• 负责人: Celina Juliano
• 金额: $ 36.15万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688063
• 关键词: Adult; Animals; Basic Science; Biological Models; Body part; Cells; Cicatrix; Cnidaria; Development; Developmental Biology; Disease; Event; Foundations; Future; Genetic Transcription; Goals; Health; Human; Injury; Laboratories; Lead; Limb structure; Link; Medicine; Molecular; Natural regeneration; Pathway interactions; Process; Regenerative Medicine; Research; Resolution; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Testing; Therapeutic; Time; cell type; engineered stem cells; experimental study; gene conservation; improved; loss of function; novel; programs; regenerative; response; response to injury; single-cell RNA sequencing; stem cell differentiation; transcription factor

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.

项目摘要/摘要 在再生动物中，成年人的灾难性损伤（例如肢体损失）激活发育 发展新身体部位的途径。相反，灾难性伤害导致疤痕和功能丧失 人类。分子对损伤的反应在动物中是保守的，无论其再生能力如何 一个关键的开放问题是了解为什么伤害反应激活某些人的发育途径 动物，但没有其他动物。我们的长期目标是回答这个问题，这要求我们破译 受伤引起的转录因子与发展计划之间的调节联系 再生动物。这应该通过细胞分辨率来完成，因为细胞类型对 受伤并在再生过程中具有不同的作用。为了实现我们的目标，我们研究了简单的Cnidarian Hydra 庸俗，因为成年人既显示不断积极的稳态发展又有再生 响应灾难性损伤的发展；这使我们能够剖析体内平衡和再生 并行开发，并在两者之间进行直接比较和连接。因此我们的实验室 有两个主要的研究方向：1）阐明驱动的信号通路和转录网络 稳态发展和2）确定伤害信号如何触发这些发育计划 再生。要了解体内稳态的开发，我们使用单细胞RNA-seq（SCRNA-Seq）捕获所有 成年人的细胞状态，包括分化过程中的细胞。我们将细胞置于发展中 识别在关键发展决策点表达的转录因子的轨迹，我们将测试 使用功能实验。此外，我们将在信号通路后重复SCRNA-SEQ实验 扰动确定这些途径如何控制稳态动物中的细胞类型规范。到 了解再生的发展，我们已经确定了受伤引起的转录因子及其推定因素 监管目标。我们将测试这些转录因子的功能，以进行调节 伤害反应与发展计划之间的联系。此外，我们将执行SCRNA-SEQ 和对再生时间课程的轨迹分析，以获得对细胞规范的全球理解 再生发展期间的事件。我们的研究计划将提高对基本的理解 发展生物学过程，这将对人类健康产生积极影响，因为：1） 细胞类型规范最终导致疾病，因此了解正常发育的发生方式有所了解 我们对疾病的理解，2）治疗医学菜肴中的工程干细胞分化依赖 关于有关开发模型系统中的细胞规范的基本发现，以帮助指导 实验，以及3）了解某些动物的伤害与发育之间的联系如何 但是，没有其他人是利用这种能力以使治疗医学受益的关键。

项目成果

Generic injuries are sufficient to induce ectopic Wnt organizers in Hydra.

• DOI: 10.7554/elife.60562
• 发表时间: 2021-03-29
• 期刊: eLife
• 影响因子: 7.7
• 作者: Cazet JF;Cho A;Juliano CE
• 通讯作者: Juliano CE

High Intrinsic Oncogenic Potential in the Myc-Box-Deficient Hydra Myc3 Protein.

• DOI: 10.3390/cells12091265
• 发表时间: 2023-04-26
• 期刊: Cells
• 影响因子: 6

Differentiation trajectories of the Hydra nervous system reveal transcriptional regulators of neuronal fate.

水螅神经系统的分化轨迹揭示了神经元命运的转录调节因子。

• DOI: 10.1101/2023.03.15.531610
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Primack,AbbyS;Cazet,JackF;Little,HannahMorris;Mühlbauer,Susanne;Cox,BenD;David,CharlesN;Farrell,JeffreyA;Juliano,CelinaE
• 通讯作者: Juliano,CelinaE

Differential gene regulation in DAPT-treated Hydra reveals candidate direct Notch signalling targets.

DAPT 处理的 Hydra 中的差异基因调控揭示了候选的直接 Notch 信号传导靶点。

• DOI: 10.1242/jcs.258768
• 发表时间: 2021
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Moneer,Jasmin;Siebert,Stefan;Krebs,Stefan;Cazet,Jack;Prexl,Andrea;Pan,Qin;Juliano,Celina;Böttger,Angelika
• 通讯作者: Böttger,Angelika