Molecular and cellular mechanisms underlying the nerve dependence of regeneration

神经再生依赖性的分子和细胞机制

• 批准号: 10684856
• 负责人: Maria Antonietta Tosches
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684856
• 关键词: Adult; Ambystoma; Amphibia; Anatomy; Animals; Behavior; Biological Metamorphosis; Biology; Body part; Brain; Cell Communication; Cells; Comparative Study; Complement; Complex; Dependence; Development; Environment; Evolution; Foundations; Gene Transfer Techniques; Genes; Genome; Goals; Human; Life; Life Cycle Stages; Limb structure; Link; Mediating; Methods; Molecular; Natural regeneration; Nerve; Nervous System; Newts; Organ; Pathology; Physiological; Physiology; Pleurodeles; Property; Protein Secretion; Regenerative Medicine; Regenerative capacity; Research; Salamander; Signal Induction; Time; Tissue-Specific Gene Expression; Tissues; Vertebrates; Work; cell type; genome editing; limb regeneration; neural; neurotransmission; novel strategies; programs; regeneration model; regenerative; rib bone structure; stem cell proliferation; stem cells

PROJECT SUMMARY Cells are the building blocks of life. The functions of tissues and organs emerge from the dynamic properties and interactions of cell types. The diversity of cell types and cellular states, over time scales ranging from minutes to millennia, underlies the anatomical and physiological diversity of animals. Because cellular diversity is ultimately the result of differential gene expression, studying organismal biology from a cell type perspective is necessary to link genes to animal physiology and pathology. The overarching goal of our research program is to understand how the molecular diversity and evolution of cell types determines how vertebrate species adapt differently to changes in their environment. We focus on problems where the evolutionary perspective has the potential to reveal fundamental principles that may generalize across species. A smaller part of the lab investigates the relationships between cell type evolution and the evolution of behavior. The majority of the lab focuses on regeneration, to elucidate how dynamic interactions of cell types in space and time result in the regeneration of complex tissues and body parts, with an emphasis on those cell types and interactions that might be conserved across body parts and species. Our goal for the next five years is to lay the foundations of this research program. Specifically, we propose to develop further the Spanish ribbed newt Pleurodeles waltl as a model for regeneration. Urodele amphibians such as newts are the terrestrial vertebrates with the highest regenerative capacity. Pleurodeles is an excellent complement to axolotl, the most popular amphibian model for regeneration: (i) these two species diverged about 150 million years ago, and their comparison may reveal fundamental principles of regeneration; (ii) unlike axolotl, Pleurodeles has a complete life cycle, including metamorphosis into a true adult stage; (iii) Pleurodeles has a sequenced genome and established methods for transgenesis and genome editing. To maximize the impact of our research and discover evolutionarily conserved mechanisms, we will focus on the nerve dependence of regeneration, a phenomenon observed in almost every highly-regenerative species and in a variety of tissues. Specifically, we will compare brain and limb regeneration. First, we will determine whether regeneration depends on the same neural secreted proteins in these two different contexts. Second, we will clarify whether neural activity is necessary to mediate the effects of nerves on regeneration. Third, we will decipher how neural signals induce the proliferation of stem or progenitor cells. Impact: this work will reveal molecular and cellular mechanisms of regeneration that generalize across body parts, and lay the foundation for comparative studies across species. The discovery of general mechanisms underlying regeneration will clarify why many species, including humans, have lost regenerative capacity, and may catalyze the development of new approaches for human regenerative medicine.

项目摘要 细胞是生命的基础。组织和器官的功能从动态特性中出现 细胞类型的相互作用。细胞类型和细胞状态的多样性，随着时间的流逝，范围从分钟到 几千年来，动物的解剖学和生理多样性是基础。因为蜂窝多样性最终是 差异基因表达的结果，从细胞类型的角度研究生物学是必要的 将基因与动物生理和病理联系起来。我们研究计划的总体目标是 了解分子多样性和细胞类型的演变如何决定脊椎动物物种如何适应 与环境变化不同。我们专注于进化观点具有的问题 揭示可能跨越物种的基本原理的潜力。实验室的较小部分 研究细胞类型演化与行为演变之间的关系。实验室的大多数 专注于再生，以阐明细胞类型在时空中的动态相互作用如何导致 复杂组织和身体部位的再生，重点是这些细胞类型和相互作用 在身体部位和物种之间保守。 我们接下来五年的目标是为该研究计划奠定基础。具体来说，我们建议 进一步发展西班牙肋骨纽特胸膜waltl作为再生的典范。 Urodele两栖动物这样 因为纽约是陆生脊椎动物，其再生能力最高。 Pleurodeles是一个很好的 补充Axolotl是最受欢迎的两栖动物模型的再生：（i）这两个物种围绕 15000万年前，它们的比较可能揭示了再生的基本原则； （ii）与Axolotl不同， 胸腔具有完整的生命周期，包括变形为真正的成年阶段。 （iii）Pleurodeles有一个 测序的基因组和已建立的转基因和基因组编辑方法。 为了最大化我们的研究的影响并发现进化保守的机制，我们将重点关注 再生的神经依赖性，几乎在所有高度再生物种中都观察到的现象 并在多种组织中。具体而言，我们将比较大脑和肢体再生。首先，我们将确定 在这两种不同的情况下，再生是否取决于相同的神经分泌蛋白。第二， 我们将阐明是否需要神经活动来介导神经对再生的影响。第三，我们 将破译神经信号如何诱导茎或祖细胞的增殖。 影响：这项工作将揭示再生的分子和细胞机制，这些机制遍布体内 零件，并为跨物种的比较研究奠定基础。一般机制的发现 潜在的再生将阐明为什么包括人类在内的许多物种失去了再生能力，而 可能会促进人类再生医学新方法的发展。