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.

项目概要 细胞是生命的基石。组织和器官的功能源于其动态特性和 细胞类型的相互作用。细胞类型和细胞状态的多样性，从几分钟到几分钟不等。 几千年来，构成了动物解剖学和生理学多样性的基础。因为细胞多样性最终是 差异基因表达的结果，从细胞类型的角度研究生物体生物学是必要的 将基因与动物生理学和病理学联系起来。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进化如何决定脊椎动物物种的适应方式 与环境的变化不同。我们关注的是进化论视角下的问题 揭示可普遍适用于物种的基本原理的潜力。实验室的一小部分 研究细胞类型进化与行为进化之间的关系。实验室的大部分 专注于再生，阐明细胞类型在空间和时间上的动态相互作用如何导致 复杂组织和身体部位的再生，重点是那些可能的细胞类型和相互作用 在身体部位和物种之间保持保守。 我们未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 进一步开发西班牙肋蝾螈 Pleurodeles waltl 作为再生模型。有尾目两栖动物如 因为蝾螈是具有最高再生能力的陆生脊椎动物。侧耳菜是一种优秀的 对蝾螈（最流行的两栖动物再生模型）的补充：（i）这两个物种的分歧在于 1.5亿年前，它们的比较可能揭示再生的基本原理； (ii) 与蝾螈不同的是， 侧耳目有一个完整的生命周期，包括变态到真正的成虫阶段； (iii) 侧耳目有一个 测序基因组并建立转基因和基因组编辑方法。 为了最大限度地发挥我们研究的影响并发现进化上保守的机制，我们将重点关注 再生的神经依赖性，几乎在每个高度再生的物种中都观察到这种现象 以及各种组织中。具体来说，我们将比较大脑和肢体的再生。首先，我们将确定 再生是否取决于这两种不同环境中相同的神经分泌蛋白。第二， 我们将阐明神经活动是否是介导神经对再生的影响所必需的。第三，我们 将破译神经信号如何诱导干细胞或祖细胞的增殖。 影响：这项工作将揭示全身再生的分子和细胞机制 部分，为跨物种比较研究奠定基础。一般机制的发现 潜在的再生将解释为什么包括人类在内的许多物种已经失去了再生能力，并且 可能会促进人类再生医学新方法的发展。