权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Chromatin Regulation of Tissue Regeneration and Stem Cell Function

组织再生和干细胞功能的染色质调节

基本信息

批准号：
10650765
负责人：
Elizabeth Marie Duncan
金额：
$ 37.85万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650765
关键词：
Adult Animal Model Animals Biochemical Biological Process Cells Chromatin Cilia Complex Cues Custom Data Development Developmental Process Dissociation Embryonic Development Enzymes Epithelium Essential Genes Event Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genome Genomic approach Genomics Heterogeneity Injury Laboratory Study Link MLL gene Mediator Methods Molecular Natural regeneration Organism Pattern Planarians Platyhelminths Pluripotent Stem Cells Population Heterogeneity Process Proteins RNA Interference Regenerative capacity Regulation Research Role Signal Induction Signal Transduction Structure Techniques Testing Tissue Differentiation Tissues Translating Work cell type comparative comparative genomics in vivo innovation interest novel regenerative response single cell analysis stem cell function stem cells tissue regeneration trait transcription factor

项目摘要

Regeneration is a remarkable phenomenon that is both ubiquitous and mysterious; although many different animals are capable of replacing damaged and/or lost structures, it is unclear how these regenerative species maintain both the cellular stability required for tissue integrity and the cellular plasticity needed to reactivate tissue development upon injury. Moreover, as regeneration is often induced by spontaneous and imprecise tissue damage, how do cells translate broad and sudden signals into cell-type-specific transcriptional changes? Genomic regulators such as transcription factors and chromatin-modifying enzymes work together to instruct cell fate during developmental processes. Although there is substantial data describing how these factors orchestrate embryogenesis, much less is known about how they are activated to induce regeneration. My central hypothesis is that chromatin serves as a mediator between the signaling events that are triggered by significant tissue loss and the cellular changes they induce to activate regeneration. To uncover the fundamental molecular mechanisms underlying this process, my laboratory studies the planarian model of animal regeneration. Planarians are free-living flatworms with incredible regenerative capacities. They are also amenable to genetic perturbation through RNAi, easily dissociated for single cell analyses, and encode chromatin modifying proteins with strong homology to those in other organisms. We are particularly interested in how some planarian cell types respond to injury by activating specific, essential, regeneration genes, while others activate an entirely different set of loci in response to the same injury. My lab uses multiple customized methods to isolate specific planarian cell types, both differentiated and stem cells, in order to characterize the chromatin state of these cell types before and after injury. We also leverage data showing that RNAi depletion of the MLL1/2 chromatin enzyme in the planarian Schmidtea mediterranea leads to loss of cilia on its outer epithelium. In addition, we have recently isolated and characterized a new planarian species that has a unique cilia pattern on its outer epithelium, providing an exciting opportunity to use comparative genomic approaches to identify specific genes that are linked to this particular trait. Combining all these approaches, we aim to dissect the functional role and molecular signaling cues contributed by specific cell types during regeneration. The outer epithelium and other differentiated tissues are essential for planarian regeneration in large part because they signal to a population of heterogeneous multi and pluripotent stem cells that are maintained in adult planarians. Because these stem cells must differentiate into all needed cell types in response to missing tissue signals, it is not surprising that they are highly plastic and transcriptionally heterogeneous. Yet it is unknown how they create and maintain this heterogeneity in vivo. We will test the hypothesis that a conserved chromatin signature regulates this critical feature. These studies will uncover important mechanisms underlying both regeneration and other biological processes that require dynamic gene regulation across complex tissues.

再生是一种非凡的现象，既无所不在又神秘莫测；虽然有很多不同