Change of Institution

机构变更

• 批准号: 10687217
• 负责人: CAROLINE E BURNS
• 金额: $ 66.38万
• 依托单位: BOSTON CHILDREN'S 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687217
• 关键词: 22q11.2; Acute myocardial infarction; Address; Adult; Affect; Age; Award; 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; Institution; 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; Proliferating; Regenerative Medicine; Regenerative capacity; Research; Research Personnel; Role; Severities; Signal Transduction; System; Time; Zebrafish; cardiac regeneration; flexibility; gene discovery; genetic variant; human disease; human model; microdeletion; model organism; mortality; notch protein; novel; prenatal; programs; regenerative; repaired; segregation

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. !

项目摘要 心血管疾病代表了全球发病率和死亡率的第一大原因，影响了 从患有先天性心脏缺陷（CHD）到成年人的婴儿的广泛年龄段 随着时间的流逝，急性心肌梗死和/或发展充血性心力衰竭。我的研究计划是 由我们可以使用斑马鱼模型有机体理解的简单假设的动机 分子和细胞水平如何在发育过程中建立心血管系统及其如何建立 在成年期间再生。在这里，我计划利用长期支持并增加科学支持 NHLBI R35新兴调查员奖提供的灵活性，以继续并扩大我的实验室的两个 主要研究集中于伟大的血管形态发生和心脏再生，以应对重大挑战 在每个字段。具体而言，我将使用斑马鱼系统的遗传和再生属性：（1）建模 破坏伟大船只建立的人类疾病以及（2）发现哺乳动物心脏的关键障碍 再生。关于前者，我们进行了有关细胞的范式转移观察结果 Digeorge综合征患者中存在的心血管表型的病因 染色体22q11.2上的半合子微缺失，该区域具有TBX1基因。我们计划探究 深入这些细胞机制，并通过识别与生物学相关的靶标的新基础 TBX1转录复合物使用专有的冠状斑马鱼菌株。由于约有20％的人携带 22q11.2缺失缺乏任何可辨认的病理学，我们预计我们发现的基因是TBX1 转录目标将代表深刻影响DG的严重性的新型候选人 心血管缺陷。我们还计划创建新的CHD模型，以链接先前确定的遗传 在新生儿中与大血管分离的变体与病理学并揭示细胞和 疾病的分子基础。拟议研究的结果将对我们的基金产生重大贡献 知识并可能影响遗传咨询，产前诊断和可能的产前修复。 此外，我们在再生斑马鱼中发现了心肌增殖的新型决定剂 可能导致包括人类在内的哺乳动物心中观察到的再生失败的心。 具体而言，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改变如何影响心肌细胞 增殖，并确定心肌倍性是否影响再生能力。结果 拟议的研究将直接指导未来的方法哄骗哺乳动物心脏再生 疤痕并确定对再生医学的实践进攻。 呢

项目成果

Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration.

• DOI: 10.1161/circulationaha.117.030801
• 发表时间: 2018-05-15
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Natarajan N;Abbas Y;Bryant DM;Gonzalez-Rosa JM;Sharpe M;Uygur A;Cocco-Delgado LH;Ho NN;Gerard NP;Gerard CJ;MacRae CA;Burns CE;Burns CG;Whited JL;Lee RT
• 通讯作者: Lee RT

Innate Mechanisms of Heart Regeneration.

心脏再生的先天机制。

• DOI: 10.1101/cshperspect.a040766
• 发表时间: 2021
• 期刊: Cold Spring Harbor perspectives in biology
• 影响因子: 7.2
• 作者: Yin,Hui-Min;Burns,CGeoffrey;Burns,CarolineE
• 通讯作者: Burns,CarolineE

TGF-β Signaling Is Necessary and Sufficient for Pharyngeal Arch Artery Angioblast Formation.

• DOI: 10.1016/j.celrep.2017.07.002
• 发表时间: 2017-07-25
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Abrial M;Paffett-Lugassy N;Jeffrey S;Jordan D;O'Loughlin E;Frederick CJ 3rd;Burns CG;Burns CE
• 通讯作者: Burns CE

Ruvbl2 Suppresses Cardiomyocyte Proliferation During Zebrafish Heart Development and Regeneration.

• DOI: 10.3389/fcell.2022.800594
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Sharpe M;González-Rosa JM;Wranitz F;Jeffrey S;Copenhaver K;Burns CG;Burns CE
• 通讯作者: Burns CE

Zebrafish heart regeneration: 15 years of discoveries.

• DOI: 10.1002/reg2.83
• 发表时间: 2017-06
• 期刊: Regeneration (Oxford, England)
• 作者: González-Rosa JM;Burns CE;Burns CG
• 通讯作者: Burns CG