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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：
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的附肢。相比之下，成年哺乳动物四肢的再生愈合仅限于脚趾的尖端。的关键挑战之一发育生物学的目的是了解组织再生是如何以及为什么发生的。四肢或鳍的特征再生是胚基的形成，胚基是一种间充质结构，含有用于新骨骼的祖细胞。元素随着再生的进行，芽基细胞增殖和模式化受到调节，使得丧失的细胞数量减少。替换尺寸和形状正确的组织。虽然已定义的细胞动力学和分子生物学的目录组织再生的因素正在扩大，我们对参与再生事件的基因知之甚少在受伤后订婚。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，这些序列是如何分布在整个基因组的组织再生过程中，有再生能力的动物，什么是转录因子参与这些序列？最近，我们鉴定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，可以在简单的构建体中进行工程改造，以表达促进生长的发育因子。再生，并具有被远缘物种的转录机制识别的潜力。的这项提案的总体目标是发现基因调控概念和机制，与截肢的肢体吻合我们将检验增强子和沉默子是关键的假设调节模块，使附属物再生在斑马鱼。这项工作将增加对脊椎动物组织再生过程中的发育调控，为研究理解，也许是改变，人类组织再生能力的现有限制。