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Molecular and Genetic Analysis of Fin Regeneration in Zebrafish

斑马鱼鳍再生的分子和遗传分析

基本信息

批准号：
10795204
负责人：
Junsu Kang
金额：
$ 24.64万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY FOR PARENT GRANT R35GM137878 Regenerative capacity is widespread throughout almost all animal phyla, but the distributing pattern appears to be inexplicable. This diverse regenerative distribution raises questions of how animals evolve toward loss or gain of regenerative capacity and of what cellular and molecular mechanisms control regenerative ability. One feature of regeneration is that innervation is essential for peripheral tissue regeneration. Previous studies have shown that nerves are involved in multiple regeneration processes from early to late regenerative events and that distinct neuronal subtypes, such as cholinergic and sensory neurons, play different roles during tissue regeneration. However, whether neuronal excitation is required for tissue regeneration and which neuronal subtypes are associated with these processes remains poorly known. Obtaining a genetically amenable animal model will uniquely permit the identification of the essential neuronal subtypes and establishing their roles in tissue regeneration. Through forward genetic screening to discover novel regeneration-associated genes, we recently discovered a new zebrafish mutant exhibiting locomotion disorder and impaired fin regeneration in a temperature-dependent manner. Whole-exome sequencing and further fine genetic mapping analysis identified a missense mutation in the scn8a gene, which encodes the major neuronal voltage-gated sodium channel Nav1.6. We will develop a new paradigm for ion channel-regulated tissue regeneration. We will take advantage of the temperature sensitivity of scn8a mutation to define how scn8a mutation influences locomotion behavior and multiple regenerative processes. We will elucidate principles for neurons as essential drivers of tissue regeneration. We will address the challenge of whether neuronal Scn8a is required for locomotion and tissue regeneration and which Scn8a expressing neuronal subtypes are associated with fin regenerative processes. In addition to scn8a mutant, we will investigate the other two mutants, each of which exhibits either fin re-growth defects or impaired re-patterning, to uncover unidentified regeneration-associated genes and underlying mechanisms. The proposed study will construct genetic models for tissue regeneration, leading to the discovery of valuable genes regulating tissue regeneration and establishment of regenerative networks.

专利授权R35GM137878项目总结再生能力在几乎所有的动物门中都很普遍，但其分布模式似乎无法解释这种多样化的再生分布提出了动物如何进化到损失或收益的问题再生能力以及控制再生能力的细胞和分子机制。一个特征神经支配是外周组织再生所必需的。先前的研究表明神经参与从早期到晚期再生事件的多个再生过程，神经元亚型（例如胆碱能和感觉神经元）在组织再生过程中发挥不同的作用。然而，组织再生是否需要神经元兴奋以及哪些神经元亚型是与这些过程相关的知识仍然很少。获得一个遗传上适合的动物模型将独特地允许鉴定必需的神经元亚型并确定它们在组织中的作用再生通过正向遗传筛选发现新的再生相关基因，我们最近发现了一种新的斑马鱼突变体，表现出运动障碍和鳍再生受损，温度依赖的方式。全外显子组测序和进一步的精细遗传图谱分析确定编码主要神经元电压门控钠通道的scn8a基因的错义突变导航1.6。我们将开发一种新的离子通道调控组织再生的范例。我们将利用 scn8a突变的温度敏感性，以确定scn8a突变如何影响运动行为和多种再生过程。我们将阐明神经元作为组织的基本驱动力的原则再生我们将讨论神经元Scn8a是否是运动和组织所必需的挑战。 Scn8a表达神经元亚型与鳍再生过程相关。在除了scn8a突变体，我们将研究另外两个突变体，每个突变体都表现出鳍的再生长，缺陷或受损的重新模式，以揭示未识别的再生相关基因和潜在的机制等这项拟议中的研究将构建组织再生的遗传模型，调节组织再生和建立再生网络的有价值的基因。