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

Investigating the contributions of neural crest to adult regeneration

研究神经嵴对成人再生的贡献

基本信息

批准号：
10646192
负责人：
Megan Lee Martik
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646192
关键词：
Ablation Adult Advisory Committees Area Award Biological Biological Assay Biology Biotinylation Cardiac Cardiac Myocytes Cardiovascular system Cell Reprogramming Cells Cellular biology ChIP-seq Chemotactic Factors Chemotaxis Cicatrix Cues Data Data Set Development Developmental Biology Developmental Gene Ectoderm Embryo Event Excision Fishes Foundations Future Gene Expression Profile Genes Genome Goals Heart Heart Injuries Heart failure Human Hypertrophic Cardiomyopathy In Vitro Injury Mammals Mediating Mentors Mesoderm Migration Assay Myocardial Natural regeneration Neural Crest Neural Crest Cell Neurophysiology - biologic function Nitroreductases Operative Surgical Procedures Pathway interactions Phase Play Population Process Proliferating Publishing Regenerative capacity Regulator Genes Research Resolution Role Site Source System Techniques Testing Thallium Myocardial Perfusion Imaging Stress Test Therapeutic Time Tissues Transgenic Organisms Work Zebrafish cardiac regeneration cardiac repair cell motility cell regeneration cell type droplet sequencing experimental study gene network gene regulatory network genetic signature heart damage high resolution imaging inducible Cre injured insight lens migration multidisciplinary nerve injury neuromechanism programs regeneration potential repaired response to injury single-cell RNA sequencing skills tissue regeneration transcriptome sequencing wound

项目摘要

PROJECT SUMMARY/ ABSTRACT: Cardiac neural crest cells are crucial for the development of the cardiovascular system by contributing to a small proportion of cardiomyocytes of the adult heart. This unique population of neural crest-derived cardiomyocytes represents an appealing source of precursor-like cells able to control myocardial regeneration. My published and preliminary data show that upon injury sox10+ cells expand in an injury-induced proliferative manner and are required for successful regeneration by initiating a developing neural crest gene regulatory network. While preliminary results suggest it is likely these cells are derived from a neural crest origin, this has yet to be explored at great depth. Previous studies of cardiac regeneration have focused primarily on mesoderm- derived populations, and, now, much remains to be uncovered about the role of ectoderm-derived neural crest cells in the repair process. With this Pathway to Independence Award, I will seek to understand the underlying mechanisms of neural crest contributions to adult heart repair using cell biological approaches, systems-level techniques, and high-resolution imaging of regenerating hearts. The overall objectives of this proposal are to test the hypothesis that neural crest-derived cells are required for heart regeneration in zebrafish (Aim 1), use single cell RNA-seq and ChIP-seq to look for subpopulations of neural crest-derived cells that express distinct gene signatures in response to injury (Aim 2), and investigate, at high-resolution, the morphogenetic events that allow adult sox10+ cells to contribute to the injury response (Aim 3). The central hypothesis of this proposal is that neural crest-derived cells play an essential role in heart regeneration by redeploying a developmental neural crest program. The long term goal of this project is to understand how developmental programs are reused for regeneration in the adult body and how we can hijack these gene regulatory circuits for reprogramming cell types that do not regenerate in order to have a more regenerative potential. The work proposed in this Pathway to Independence Award proposal will be greatly facilitated by my multi-disciplinary advisory committee with expertise in tissue regeneration, single cell RNA-seq approaches and analyses, and genome biology. After developing a formidable skillset and research foundation afforded by the two years of the mentored phase of this award, my goal is to establish a high impact, independent research group that will combine systems-level approaches with state-of-the-art cell and developmental biology techniques to answer questions of regeneration through a developmental lens. Long term project hypotheses are focused on how we can regenerate the human heart. My preliminary data shows cardiac neural crest cells contribute to cardiomyocytes not only in fish but also in amniotes; therefore, the mechanisms that stimulate these cells to contribute to regeneration in zebrafish may offer therapeutic approaches to repair heart damage in mammals including humans.

项目摘要/摘要：心脏神经嵴细胞对心血管系统的发育至关重要，它有助于成人心脏的一小部分心肌细胞。这种独特的神经嵴群体心肌细胞是能够控制心肌再生的前体样细胞的一个有吸引力的来源。我发表的初步数据表明，在受伤时，sox10+ 细胞会在损伤诱导的增殖中扩张。方式，并且是通过启动发育中的神经嵴基因调节来成功再生所必需的网络。虽然初步结果表明这些细胞很可能来自神经嵴起源，但这已经尚待深入探讨。先前关于心脏再生的研究主要集中在中胚层衍生的人群，现在，关于外胚层衍生的神经嵴的作用仍有许多待揭示细胞修复过程中。通过这个独立之路奖，我将努力了解其背后的意义使用细胞生物学方法、系统水平神经嵴对成人心脏修复的贡献机制技术和再生心脏的高分辨率成像。该提案的总体目标是检验斑马鱼心脏再生需要神经嵴衍生细胞的假设（目标 1），使用单细胞 RNA-seq 和 ChIP-seq 寻找表达不同的神经嵴衍生细胞亚群响应损伤的基因特征（目标 2），并以高分辨率研究形态发生事件允许成年 sox10+ 细胞参与损伤反应（目标 3）。该提案的中心假设是神经嵴衍生细胞通过重新部署发育神经在心脏再生中发挥重要作用波峰计划。该项目的长期目标是了解如何重用开发程序成人体内的再生以及我们如何劫持这些基因调控电路来重新编程细胞类型不再生以获得更大的再生潜力。本途径中提出的工作我的多学科顾问委员会将极大地促进独立奖提案的制定组织再生、单细胞 RNA-seq 方法和分析以及基因组生物学方面的专业知识。后两年的指导阶段提供了强大的技能和研究基础奖项，我的目标是建立一个高影响力的独立研究小组，将系统级采用最先进的细胞和发育生物学技术来回答再生问题通过发展的视角。长期项目假设的重点是我们如何使人类再生心。我的初步数据显示，心脏神经嵴细胞不仅对鱼类的心肌细胞有贡献，而且对心肌细胞也有贡献。在羊膜动物中；因此，刺激这些细胞促进斑马鱼再生的机制可能是提供修复包括人类在内的哺乳动物心脏损伤的治疗方法。