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Regulation of Appendage Regeneration in Zebrafish

斑马鱼附肢再生的调控

基本信息

批准号：
10194281
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/10194281
关键词：
Adult Alleles Amphibia Amputation Animals Binding Biological Cardiac Catalogs Cell Proliferation Cells Chemicals Chromatin Code Complex DNA DNA Sequence Development Developmental Biology Digit structure Distal Distant Elements Embryonic Development Engineering Enhancers Event Financial compensation 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 base blastema 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.

成年硬骨鱼和尾形两栖动物可以再生整个被切除的附属物。相比之下,