Genetic circuitry governing heart growth and repair

控制心脏生长和修复的遗传电路

• 批准号: 10565925
• 负责人: Guo Huang
• 金额: $ 55.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565925
• 关键词: Acute; Adrenergic Receptor; Adult; Animals; Applications Grants; B-Cell Activation; B-Cell Lymphoma 6 Protein; BCL6 gene; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Cycle Arrest; Cell Cycle Regulation; Chemicals; Clinical Treatment; Data; Development; Evolution; Genes; Genetic; Genetic Models; Growth; Heart; Heart Diseases; Heart failure; Heterocephalus; Human; Image; Injury; Knowledge; Light; Loss of Heterozygosity; Mammals; Methods; Microscopy; Mole Rats; Mus; Mutant Strains Mice; Myocardial Infarction; Nerve; Newborn Infant; Pathway interactions; Patients; Phenotype; Phylogeny; Physiological; Process; Proliferating; Publishing; Receptor Activation; Regenerative capacity; Regulation; Reporting; Repression; Rodent; Role; Science; Signal Transduction; Stains; Thermogenesis; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Transcription Repressor; United States; Up-Regulation; Viral Vector; Weight; Withdrawal; Work; Zebrafish; cardiac regeneration; cardiac repair; coronary fibrosis; differential expression; experimental study; heart dimension/size; heart function; hormonal signals; improved; inhibitor; injury and repair; insight; ischemic injury; mortality; mouse genetics; mutant; myocardial injury; novel; organ regeneration; postnatal; regeneration potential; regenerative repair; repaired; response to injury; self-renewal; synergism; transcription factor; transcriptome sequencing; treatment strategy

Project Summary/Abstract Current available clinical treatments greatly reduced the acute mortality of myocardial infarction. However, lost cardiomyocytes during myocardial injury still cannot be replenished, leading to a steady increase of heart failure patients. In contrast, adult zebrafish and newborn mammals are capable of robust cardiac regeneration. This process has been shown to rely on proliferation of preexisting cardiomyocytes after injury. In rodents, such an ability is lost within the first week after birth when the majority of cardiomyocytes undergo permanent cell-cycle arrest. However, the physiological triggers of this transition remain largely unknown. Our recently published work suggests that activation of thermogenic pathways during the acquisition of endothermy in ontogeny and phylogeny may cause a loss of cardiomyocyte proliferative and regenerative capacity (Hirose et al., 2019 Science). Following this direction, we discover that increases of neurohormonal activities associated with postnatal thermogenesis drive cardiomyocyte cell-cycle exit, at least in part by turning on B cell lymphoma 6 (Bcl6), a transcription factor previously unappreciated in the heart field. Moreover, Bcl6 is also identified in our RNA-seq analysis of all 1179 annotated mouse transcription factors as one of the top candidates that may induce postnatal loss of cardiac regenerative potential. Intriguingly, cardiac expression of Bcl6 increases 19 folds after birth in mice but not in naked mole-rats (Heterocephalus glaber), a poikilothermic rodent. The function of Bcl6 in cardiomyocytes have never been reported. Our preliminary data show that cardiomyocyte- specific deletion of Bcl6 in mice leads to enhanced cardiomyogenesis both in heart growth and after ischemic injury. We further identify a putative direct target gene of Bcl6, and demonstrate its major contribution to the phenotypes through genetic rescue experiments in mice. Based on these results, this grant proposal will apply a novel method that integrates whole-heart clearing, immunostaining and volume imaging by light-sheet microscopy to accurately assess the total cardiomyocyte number, and exploit mouse genetic models to elucidate the functions of Bcl6 and its downstream target in cardiomyocyte cell-cycle control during postnatal heart growth and adult myocardial injury repair. The regulation of Bcl6 in ontogeny and its expression in phylogeny will be further investigated to understand whether and how its expression increases in parallel with the development and evolution of endothermy. Altogether, this work will yield significant knowledge about the physiological brake of cardiac regeneration, and may offer novel treatment strategies to enhance heart regenerative repair in adult mammals.

项目摘要/摘要 目前可用的临床治疗方法大大降低了心肌梗死的急性死亡率。然而，迷失了 心肌损伤期间的心肌细胞仍不能得到补充，导致心脏稳步增加 失败的病人。相比之下，成年斑马鱼和新生哺乳动物的心脏再生能力很强。 这一过程已被证明依赖于损伤后原有心肌细胞的增殖。在啮齿动物身上， 这种能力在出生后的第一周内就会丧失，那时大多数心肌细胞会经历永久性的 细胞周期停滞。然而，这种转变的生理触发因素在很大程度上仍不清楚。我们最近 已发表的工作表明，在获得吸热的过程中，产热途径被激活 个体发育和系统发育可能导致心肌细胞增殖和再生能力的丧失(Hirose et Al.，2019 Science)。沿着这个方向，我们发现神经激素活动的增加与 出生后产热导致心肌细胞周期退出，至少部分是通过启动B细胞淋巴瘤 6(Bcl6)，一种以前在心脏领域未被发现的转录因子。此外，Bcl6也在 我们对所有1179个带注释的小鼠转录因子的rna-seq分析是可能的首选候选因子之一 导致心脏再生能力在出生后丧失。耐人寻味的是，Bcl6的心脏表达增加了19 在小鼠出生后折叠，但在裸鼠(光头异头鼠)中不折叠，这是一种变温啮齿动物。这个 Bcl6在心肌细胞中的功能尚未见报道。我们的初步数据显示心肌细胞- 小鼠Bcl6基因的特异性缺失导致心脏生长和缺血后心肌生成增强 受伤。我们进一步确定了Bcl6的一个可能的直接靶基因，并证明了它在 通过小鼠的遗传拯救实验进行表型分析。根据这些结果，这项赠款提案将适用于 一种集全心清除、免疫染色和光片体积成像于一体的新方法 显微镜准确评估心肌细胞总数，并利用小鼠遗传模型 Bcl6及其下游靶点在生后心肌细胞周期调控中的作用 心脏发育与成人心肌损伤修复。Bcl6在个体发育中的调控及其在卵巢癌中的表达 系统发育将进一步研究，以了解它的表达是否以及如何同时增加 吸热学的发展和进化。总之，这项工作将产生关于 心脏再生的生理性刹车，并可能提供新的治疗策略来增强心脏 成年哺乳动物的再生修复。