Understanding Spinal Cord Regeneration; the role of dynamic gene expression

了解脊髓再生；

• 批准号: MR/X020754/1
• 负责人: Ximena Soto
• 金额: $ 189.92万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX020754%2F1
• 关键词: Understanding; Spinal; Cord; Regeneration; role

Animals at embryonic stages are capable of reconstructing functional tissue after disruptive injuries. Extensive research in the field of regenerative medicine aims to understand the similarities between embryogenesis and regeneration programs and despite great advances in the last few decades, many aspects of the biological and molecular mechanisms remain unknown. Mammals, including humans, cannot replace lost neurons after spinal cord injury (SCI), whereas zebrafish can regenerate neurons to replace those that are lost after injury. Upon injury, neural stem cells initiate proliferation and generate new neurons in species with regenerative capacity, but in mammals, only cells that contribute to scar formation are generated. My own research has shown that during development the generation of new neurons (neurogenesis), genes are not simply on or off. Instead, the levels of some genes pulse dynamically over time, influenced by specific factors, and control whether the cells decide to stay as proliferating neural stem cell or become new neurons. It is known that the same genes are important during spinal cord regeneration (SCR) but how they work isn't known. Therefore, it is not clear whether during SCR and the generation of new neurons are also controlled by the pulses in gene activity. Elucidating the dynamic signals and mechanisms leading to successful SCR in an animal with regenerative capacity will generate important and valuable outcomes that can be tested in higher organisms. Zebrafish is a powerful, tractable and robust animal model able to achieve functional neural regeneration following SCI, characterised by de novo neurogenesis and regrowth of neuronal connections. In this proposal I will be using larvae zebrafish as an experimental model, taking advantage of its regenerative capacity and its amenability to genetic manipulation. I will use state-of-the art live imaging techniques that show gene activity in real time. I will introduce genetic changes to assess the functional importance of pulsatile gene activity when neural stem cells undertake neuronal decisions during SCR. I will investigate how changes on pulsatile gene activity can affect the genetic landscape and alter cell-fate decisions over time during SCR. Addressing the functional importance of pulsatile gene activity during cell-fate decisions in SCR, will provide insights with potential translational implications for SCI in animals with no regenerative capacity, such as mice and humans.

处于胚胎阶段的动物能够在破坏性损伤后重建功能组织。再生医学领域的广泛研究旨在了解胚胎发生和再生程序之间的相似性，尽管在过去几十年中取得了巨大进展，但生物学和分子机制的许多方面仍然未知。包括人类在内的哺乳动物无法取代脊髓损伤（SCI）后丢失的神经元，而斑马鱼可以再生神经元来取代损伤后丢失的神经元。损伤后，神经干细胞开始增殖，并在具有再生能力的物种中产生新的神经元，但在哺乳动物中，仅产生有助于瘢痕形成的细胞。我自己的研究表明，在新神经元的产生（神经发生）的发育过程中，基因并不是简单的开或关。相反，一些基因的水平随着时间的推移而动态变化，受到特定因素的影响，并控制细胞决定作为增殖的神经干细胞还是成为新的神经元。已知相同的基因在脊髓再生（SCR）过程中很重要，但它们如何工作尚不清楚。因此，目前尚不清楚在SCR期间，新神经元的产生是否也受到基因活性脉冲的控制。阐明导致具有再生能力的动物成功SCR的动态信号和机制将产生重要和有价值的结果，这些结果可以在高等生物中进行测试。斑马鱼是一种功能强大、易于处理和强大的动物模型，能够在SCI后实现功能性神经再生，其特征在于从头神经发生和神经元连接的再生长。在这个建议中，我将使用斑马鱼幼虫作为实验模型，利用其再生能力和对遗传操作的适应性。我将使用最先进的实时成像技术，显示基因活动在真实的时间。我将介绍基因的变化，以评估神经干细胞在SCR期间进行神经元决策时脉动基因活性的功能重要性。我将研究如何在脉动基因活性的变化可以影响遗传景观和改变细胞命运的决定随着时间的推移在SCR。解决SCR中细胞命运决定过程中脉动基因活性的功能重要性，将为没有再生能力的动物（如小鼠和人类）中SCI的潜在翻译影响提供见解。