Nerve Dependency of Regeneration

再生的神经依赖性

• 批准号: RGPIN-2022-03260
• 负责人: Payne, Samantha
• 金额: $ 2.26万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746259
• 关键词: Nerve; Dependency; Regeneration

While many non-mammalian species are capable of multi-tissue regeneration, the default response to injury in mammals is scarring. Many microenvironmental factors play a role in this response, requiring a complex coordination of multiple cell types. Understanding the key regulatory signals in the cellular response to injury can give insight into promoting regeneration. Innervation is essential for regeneration; peripheral nerves are one of the first structures to infiltrate into the new tissue. While there is a clear requirement of innervation for regeneration, mechanistic details in mammals are lacking, and the potential role of nerve-derived biophysical signals is unknown. The proposed research program seeks to understand the diverse roles of nerves in regeneration by investigating biophysical mechanisms of nerve-cell crosstalk in the injury microenvironment. The objectives of this research program are to identify and characterize the mechanisms by which nerves: 1) Promote wound healing via crosstalk with the wound epithelium; 2) Modulate fibroblast activity to create a regeneration-permissive environment; and 3) Contribute to progenitor cell identity during tissue patterning. Our approach will combine the use of both in vitro and in vivo mammalian models: co-culture devices to study crosstalk between peripheral nerves and other cell types important for regeneration, such as keratinocytes, fibroblasts, and stem cells, and a mouse model of digit tip regeneration. We will study three potential biophysical mechanisms of nerve-mediated regeneration that have been associated with regeneration in non-mammalian models: 1) gap junction communication to regulate cell proliferation, 2) ECM remodeling to provide a regeneration-permissive environment, and 3) bioelectric signaling to regulate cell fate and patterning. We predict that input from nerves is essential at all stages of regeneration and mediates the basic cellular processes of cell migration, proliferation, and fate determination. This research program is essential for addressing significant knowledge gaps in the field of regenerative biology. The study of neural-driven cues presents a largely untapped yet powerful toolkit that will contribute to the understanding of the cellular control of regeneration. Through this research program we will identify the major cellular drivers of regeneration to develop new approaches to redirect the mammalian scarring program towards regeneration. Beyond regenerative biology, this research program provides important contributions to the field of stem cell biology and will establish our lab as a leader in the study of the basic mechanisms of regeneration.

虽然许多非哺乳动物物种能够多组织再生，但哺乳动物对损伤的默认反应是疤痕。许多微环境因素在这种反应中起作用，需要多种细胞类型的复杂协调。了解细胞对损伤反应的关键调控信号可以深入了解促进再生。神经支配对再生至关重要；周围神经是最先渗入新组织的结构之一。虽然再生对神经支配有明确的要求，但哺乳动物的机制细节缺乏，神经来源的生物物理信号的潜在作用尚不清楚。提出的研究计划旨在通过研究损伤微环境中神经细胞串扰的生物物理机制来了解神经在再生中的多种作用。本研究计划的目的是确定和描述神经的机制：1)通过与伤口上皮的串扰促进伤口愈合；2)调节成纤维细胞活性，创造一个允许再生的环境；3)在组织模式形成过程中有助于祖细胞的识别。我们的方法将结合体外和体内哺乳动物模型的使用：共培养装置来研究周围神经和其他对再生重要的细胞类型（如角质形成细胞、成纤维细胞和干细胞）之间的串扰，以及手指尖端再生的小鼠模型。我们将研究与非哺乳动物再生相关的神经介导再生的三种潜在生物物理机制：1)缝隙连接通讯调节细胞增殖，2)ECM重塑提供允许再生的环境，以及3)生物电信号调节细胞命运和模式。我们预测来自神经的输入在再生的所有阶段都是必不可少的，并介导细胞迁移、增殖和命运决定的基本细胞过程。这项研究计划对于解决再生生物学领域的重大知识缺口至关重要。神经驱动线索的研究提供了一个很大程度上尚未开发但强大的工具包，将有助于理解细胞对再生的控制。通过这项研究计划，我们将确定再生的主要细胞驱动因素，以开发新的方法，将哺乳动物疤痕程序转向再生。除了再生生物学，这个研究项目为干细胞生物学领域提供了重要的贡献，并将使我们的实验室成为再生基本机制研究的领导者。