Change of Institution

机构变更

• 批准号: 10447109
• 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/10447109
• 关键词: 22q11.2; Acute myocardial infarction; Address; Adult; Affect; Age; Animal Model; 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; 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; 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. !

项目摘要 心血管疾病是世界范围内发病率和死亡率的头号原因， 从患有先天性心脏病（CHD）的婴儿到患有先天性心脏病（CHD）的成年人， 急性心肌梗塞和/或随时间发展为充血性心力衰竭。我的研究项目是 动机是一个简单的假设，我们可以使用斑马鱼模式生物来理解一个 分子和细胞水平的心血管系统是如何建立在发展过程中， 在成年期再生。在这里，我计划利用长期支持和增加科学 NHLBI R35新兴研究者奖提供的灵活性，以继续和扩大我的实验室的两个 主要研究集中在大血管形态发生和心脏再生，以应对重大挑战 在每个领域。具体来说，我将使用斑马鱼系统的遗传和再生属性：（1）建模 破坏大血管建立的人类CHD，以及（2）揭示哺乳动物心脏的关键屏障 再生关于前者，我们已经对细胞的 DiGeorge综合征患者中存在的心血管表型的病因学， 染色体22q11.2上的半合子微缺失，该区域含有TBX 1基因。我们计划深入研究 深入研究这些细胞机制，并通过识别生物学相关的靶点来开辟新的领域。 tbx 1转录复合物使用专有敲入斑马鱼品系。大约20%的人携带 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Tbx 1 转录靶点将代表深刻影响DGS严重程度的新候选物， 心血管缺陷。我们还计划创建新的CHD模型，以将先前确定的遗传因素与CHD模型联系起来。 与新生儿大血管CHD分离的变异与病理学的关系，并揭示细胞和 疾病的分子基础拟议研究的结果将大大有助于我们的基金， 知识和可能影响遗传咨询，产前诊断，并可能产前修复。 此外，我们还发现了再生斑马鱼心肌增殖的新决定因素， 心脏可能导致在包括人类在内的哺乳动物心脏中观察到的再生失败。 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。的成果 拟议中的研究将直接指导未来诱导哺乳动物心脏再生的方法， 并确定再生医学的实际进展。 !