Cardiovascular Development and Regeneration in Zebrafish

斑马鱼的心血管发育和再生

• 批准号: 9795079
• 负责人: CAROLINE E BURNS
• 金额: $ 8.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-04-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795079
• 关键词: 22q11.2; Acute myocardial infarction; Address; Adult; Affect; Age; Animal Model; Award; Biological; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Chromatin; Chromosomes; Cicatrix; Complex; Congenital Heart Defects; Congestive Heart Failure; Defect; Development; DiGeorge Syndrome; Disease; Epigenetic Process; Etiology; Failure; Funding; Future; Genes; Genetic; Genetic Counseling; Genetic Transcription; Heart; Heart Diseases; Human; Individual; Injury; Knock-in; Knowledge; Laboratories; Link; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Myocardial; Myocardial Infarction; National Heart, Lung, and Blood Institute; Natural regeneration; Newborn Infant; Outcome; Pathology; Patients; Phenotype; Ploidies; Prenatal Diagnosis; Regenerative Medicine; Research; Research Personnel; Role; Severities; Signal Transduction; System; Time; Zebrafish; cardiac regeneration; flexibility; gene discovery; genetic variant; human disease; human model; microdeletion; mortality; notch protein; novel; prenatal; programs; regenerative; repaired

Project Summary Cardiovascular diseases represent the number one cause of morbidity and mortality worldwide, affecting a broad spectrum of ages from babies that are born with congenital heart defects (CHDs) to adults that suffer acute myocardial infarctions and/or develop congestive heart failure over time. My research program is motivated by the simple assumption that we can use the zebrafish model organism to understand on a molecular and cellular level how the cardiovascular system is established during development and how it regenerates during adulthood. Here, I plan to leverage the longer-term support and increased scientific flexibility afforded by the NHLBI R35 Emerging Investigator Award to continue and expand my laboratory’s two main research focuses in great vessel morphogenesis and heart regeneration to address significant challenges in each field. Specifically, I will use the genetic and regenerative attributes of the zebrafish system: (1) to model human CHDs that disrupt great vessel establishment and, (2) to uncover critical barriers to mammalian heart regeneration. In regards to the former, we have made paradigm-shifting observations concerning the cellular etiology of the cardiovascular phenotypes present in DiGeorge Syndrome patients that are caused by hemizygous microdeletions on chromosome 22q11.2, a region that harbors the TBX1 gene. We plan to delve deeper into these cellular mechanisms and break new ground by identifying biologically relevant targets of the Tbx1 transcriptional complex using a proprietary knock-in zebrafish strain. As ~20% of individuals carrying the 22q11.2 deletion lack any discernable pathology, we anticipate that the genes we discover as Tbx1 transcriptional targets will represent novel candidates that profoundly influence the severity of DGS cardiovascular defects. We also plan to create new CHD models in an effort to link previously identified genetic variants that segregate with great vessel CHDs in newborns to the pathology and to uncover the cellular and molecular basis of disease. The outcomes of the proposed studies will contribute significantly to our fund of knowledge and likely influence genetic counseling, pre-natal diagnosis, and possibly pre-natal repair. Additionally, we have uncovered novel determinants of myocardial proliferation in regenerating zebrafish hearts that likely contribute to the regenerative failures observed in mammalian hearts, including humans. Specifically, we plan to further explore the required role of Notch signaling in zebrafish heart regeneration, understand how alterations in the epigenetic landscape and in chromatin accessibility influence cardiomyocyte proliferation, and determine whether myocardial ploidy affects regenerative capacity. The outcomes of the proposed studies will directly guide future approaches to coax mammalian hearts towards regeneration instead of scarring and identify practical inroads for regenerative medicine. !

项目概要 心血管疾病是全球发病率和死亡率的第一大原因，影响着 从出生时患有先天性心脏病 (CHD) 的婴儿到患有先天性心脏病的成年人，年龄范围广泛 随着时间的推移，急性心肌梗死和/或发展为充血性心力衰竭。 出于一个简单的假设，我们可以使用斑马鱼模型生物来理解 分子和细胞水平心血管系统在发育过程中是如何建立的以及它是如何形成的 在这里，我计划利用更长期的支持和更多的科学知识。 NHLBI R35 新兴研究者奖提供了灵活性，可以继续并扩展我的实验室的两个项目 主要研究重点是大血管形态发生和心脏再生，以应对重大挑战 具体来说，我将利用斑马鱼系统的遗传和再生属性：（1）进行建模。 人类先心病会破坏大血管的建立，并且 (2) 揭示哺乳动物心脏的关键障碍 对于前者，我们对细胞进行了范式转变的观察。 迪乔治综合征患者心血管表型的病因学 染色体 22q11.2 上的半合子微缺失，该区域包含 TBX1 基因。 更深入地研究这些细胞机制，并通过识别生物相关的目标来开辟新天地 Tbx1 转录复合物使用专有的敲入斑马鱼品系，约 20% 的个体携带该复合物。 22q11.2 缺失缺乏任何可辨别的病理学，我们预计我们发现的基因为 Tbx1 转录靶标将代表深刻影响 DGS 严重程度的新候选者 我们还计划创建新的冠心病模型，以将先前发现的遗传缺陷联系起来。 与新生儿大血管先心病分离的变异体的病理学并揭示细胞和 疾病的分子基础。拟议研究的结果将为我们的基金做出重大贡献。 知识并可能影响遗传咨询、产前诊断以及可能的产前修复。 此外，我们还发现了再生斑马鱼心肌增殖的新决定因素 心脏可能导致哺乳动物心脏（包括人类）的再生失败。 具体来说，我们计划进一步探索Notch信号在斑马鱼心脏再生中所需的作用， 了解表观遗传景观和染色质可及性的变化如何影响心肌细胞 增殖，并确定心肌倍性是否影响再生能力。 拟议的研究将在未来指导引导哺乳动物心脏直接再生的方法 疤痕并确定再生医学的实际进展。 ！