Regulation of Appendage Regeneration in Zebrafish

斑马鱼附肢再生的调控

基本信息

批准号：
10619634
负责人：
KENNETH D POSS
金额：
$ 38.21万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619634
关键词：
Adult Alleles Amphibia Animals Binding Biological Cardiac Catalogs Cell Proliferation Cells Chemicals Chromatin Code Compensation Complex DNA DNA Sequence Dedications Development Developmental Biology Digit structure Distal Distant Elements Embryonic Development Engineering Enhancers Event Gene Duplication Gene Expression Genes Genetic Genetic Enhancer Element Genetic Transcription Genome Goals Injury Leptin Ligands Limb structure Link Mesenchymal Messenger RNA Methodology Methods Molecular Mutagenesis Names Natural regeneration Pattern Promoter Regions Proteins Regenerative capacity Regulation Regulator Genes Regulatory Element Shapes Structure Testing Tissues Trans-Activators Transcription Repressor Transcriptional Activation Transcriptional Silencer Elements Transgenic Organisms Work Zebrafish appendage blastema candidate identification chromosome conformation capture deletion analysis experimental study gene discovery genome-wide healing human tissue improved innovation insight mutant paralogous gene programs recruit regeneration potential regenerative screening skeletal stem cells teleost fish tissue regeneration tissue repair tool transcription factor

项目摘要

Adult teleost fish and urodele amphibians can regenerate entire amputated appendages. By contrast, regenerative healing of adult mammalian limbs is limited to the very tips of digits. One of the key challenges in developmental biology is to understand how and why tissue regeneration occurs. The hallmark of limb or fin regeneration is formation of a blastema, a mesenchymal structure that contains progenitor cells for new skeletal elements. As regeneration proceeds, blastemal cell proliferation and patterning are regulated such that lost tissues of correct size and shape are replaced. While the catalogue of defined cell dynamics and molecular factors in tissue regeneration is expanding, we know much less of how genes involved in regenerative events are engaged upon injury. That is, what are the DNA sequences that recruit activators (or repressors) of gene programs during tissue regeneration, how are these sequences distributed throughout the genomes of regeneration-competent animals, and what are the transcription factors that engage with these sequences? Recently, we identified a class of distal gene regulatory elements that preferentially activate gene expression during regeneration, can be engineered in simple constructs to express developmental factors that promote regeneration, and have the potential to be recognized by the transcriptional machinery of distant species. The overall goal of this proposal is to discover gene regulatory concepts and mechanisms that restore size and pattern to an amputated appendage. We will test the hypothesis that enhancer and silencer elements are crucial regulatory modules enabling appendage regeneration in zebrafish. This work will increase understanding of developmental regulation during vertebrate tissue regeneration, and provide important perspective for comprehending, and perhaps changing, the existing limitations in regenerative capacity of human tissues.

成年硬骨鱼和有尾目两栖动物可以再生整个截肢。相比之下，成年哺乳动物四肢的再生愈合仅限于指尖。的主要挑战之一发育生物学的目的是了解组织再生如何以及为何发生。四肢或鳍的标志再生是胚基的形成，胚基是一种间充质结构，其中含有新骨骼的祖细胞元素。随着再生的进行，胚细胞增殖和模式受到调节，从而失去更换尺寸和形状正确的组织。虽然定义的细胞动力学和分子目录组织再生的因素正在扩大，但我们对基因如何参与再生事件知之甚少受伤后从事工作。也就是说，招募基因激活子（或阻遏子）的 DNA 序列是什么？组织再生过程中的程序，这些序列如何分布在整个基因组中具有再生能力的动物，以及与这些序列结合的转录因子是什么？最近，我们发现了一类优先激活基因表达的远端基因调控元件在再生过程中，可以通过简单的构建来表达促进发育的因子再生，并有可能被远缘物种的转录机制识别。这该提案的总体目标是发现基因调控概念和机制，以恢复大小和截肢的图案。我们将检验增强子和消音器元素至关重要的假设实现斑马鱼附肢再生的调节模块。这项工作将增进对脊椎动物组织再生过程中的发育调控，并为理解并可能改变人体组织再生能力的现有局限性。