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

Cardiac regeneration by histone deacetylases

组蛋白脱乙酰酶促进心脏再生

基本信息

批准号：
10700815
负责人：
Deqiang Li
金额：
$ 39万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700815
关键词：
Adult Aging Apical Biochemistry Blood Vessels Cardiac Cardiac Myocytes Cell Cycle Cell Nucleus Cell division Chromatin Chromatin Remodeling Factor Cytoplasm Data Development Developmental Biology Disease Drug or chemical Tissue Distribution Embryo Epigenetic Process Epithelium Excision Goals Growth Heart Heart Diseases Heart failure Histone Deacetylase Human Impairment Knock-out Malignant Neoplasms Measures Molecular Biology Morbidity - disease rate Mus Myocardial Myocardial Infarction Natural regeneration Neonatal Nuclear Organ Outcome Pathologic Pathologic Processes Physiological Processes Polyploidy Process Proliferating Recovery Regenerative Medicine Role Signal Transduction Testing Therapeutic Zebrafish c-myc Genes cardiac regeneration cardiac repair cardiogenesis comparative experimental study heart function improved in vivo knock-down mortality mouse genetics myocardial injury myocyte-specific enhancer-binding factor 2 neonatal mice novel organ growth overexpression postnatal regeneration potential regenerative response therapeutically effective transcriptome sequencing transcriptomics tumor growth

项目摘要

Heart disease and heart failure remain the leading causes of morbidity and mortality worldwide. Adult mammalian heart demonstrates limited regenerative potential. Numerous measures, such as stimulating preexisting cardiomyocyte proliferation by activating cell cycle, have been attempted previously to induce heart regeneration, although only modest effects have been achieved to date. Adult cardiomyocytes need to undergo dedifferentiation first before proliferation, if not simultaneously. In fact, adult zebrafish heart regeneration is accomplished through both dedifferentiation and proliferation. Chromatin state and remodeling is often associated with numerous physiological or pathological processes including organ development, aging, and cancer. However, it is unclear whether epigenetics dictates cardiomyocyte proliferation capacity, or, whether harnessing epigenetics in adult cardiomyocytes stimulates proliferation. Through a comparative transcriptomic analysis of murine embryonic day (E) 14.5 hearts (proliferation active) and adult hearts (proliferation inert), we identified a number of chromatin remodeling factors including histone deacetylase 7 (HDAC7) that are enriched in E14.5 hearts but missing in adult hearts. HDAC7 belongs to Class II HDACs, which have specific tissue distributions and shuttle between the nucleus and cytoplasm in response to signals. Studies have shown that knockout of HDAC7 compromises vascular integrity during heart development, while overexpression of HDAC7 induces tumor growth and epithelial proliferation. However, the potential role of HDAC7 in cardiomyocyte proliferation is undetermined. In our preliminary studies, upon knocking down of HDAC7 in cultured neonatal mouse cardiomyocytes (NMCMs), we found that cardiomyocyte proliferation was significantly decreased. By contrast, overexpression of HDAC7 in NMCMs resulted in significant cardiomyocyte dedifferentiation and increased proliferation. Further, overexpression of HDAC7 in adult cardiomyocytes in vivo significantly induced cardiomyocyte proliferation and improved cardiac function after myocardial infarction. Based on these novel and exciting preliminary findings, we hypothesize that HDAC7 is both necessary for cardiomyocyte proliferation and sufficient to reactivate postnatal cardiomyocyte proliferative and regenerative potentials. Three aims are proposed to test our central hypothesis. Aim 1: To determine the mechanisms by which HDAC7 promotes cardiomyocyte proliferation; Aim 2: To determine whether HDAC7 is required for cardiomyocyte proliferation; Aim 3: To test whether HDAC7 overexpression promotes adult cardiomyocyte proliferation and improves heart function after myocardial injuries. We intend to achieve these goals by using a synergistic approach of mouse genetics, developmental and molecular biology, and biochemistry. Results of these experiments will establish a novel and rigorous therapeutic strategy for promoting heart regeneration and pave a new path to effective heart repair in humans.

心脏病和心力衰竭仍然是全世界发病率和死亡率的主要原因。成虫哺乳动物的心脏表现出有限的再生潜力。许多措施，如刺激先前已经尝试通过激活细胞周期来诱导先前存在的心肌细胞的增殖心脏再生，尽管到目前为止只取得了不大的效果。成年心肌细胞需要在增殖之前，如果不是同时进行的话，首先要经历去分化。事实上，成年斑马鱼的心脏再生是通过去分化和增殖来完成的。染色质状态和重塑通常与许多生理或病理过程有关，包括器官。发育、衰老和癌症。然而，尚不清楚表观遗传学是否决定了心肌细胞。增殖能力，或者，是否利用成年心肌细胞的表观遗传学刺激增殖。通过对小鼠胚胎发育日(E)14.5个心脏(增殖)的比较转录分析活跃)和成人心脏(增殖惰性)，我们确定了一些染色质重塑因子包括组蛋白脱乙酰酶7(HDAC7)，它在E14.5心脏中丰富，但在成人心脏中缺失。 HDAC7属于II类HDAC，具有特定的组织分布和穿梭于胞核和细胞质对信号的反应。研究表明，HDAC7的敲除会导致心脏发育过程中的血管完整性，而HDAC7的过表达诱导肿瘤生长和上皮细胞增殖。然而，HDAC7在心肌细胞增殖中的潜在作用尚不确定。在我们的初步研究中，在培养的新生小鼠心肌细胞中敲除HDAC7 (NMCMS)，我们发现心肌细胞增殖显著降低。相反， HDAC7在NMCM中的过表达导致心肌细胞的显著去分化和增加扩散。此外，在活体成人心肌细胞中过表达HDAC7显著诱导心肌梗死后心肌细胞增殖和心功能改善。基于这些小说令人兴奋的初步发现，我们假设HDAC7是心肌细胞所必需的增殖并足以重新激活出生后心肌细胞的增殖和再生潜力。我们提出了三个目标来检验我们的中心假设。目标1：确定机制通过HDAC7促进心肌细胞增殖；目标2：确定是否需要HDAC7 心肌细胞增殖；目标3：检测HDAC7过表达是否促进成年心肌细胞促进细胞增殖，改善心肌损伤后的心功能。我们打算通过以下方式实现这些目标使用小鼠遗传学、发育和分子生物学以及生物化学的协同方法。这些实验的结果将建立一种新的和严格的促进心脏的治疗策略再生并为人类有效的心脏修复铺平了一条新的道路。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epicardial HDAC3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway.

DOI：
10.1161/circresaha.122.320785
发表时间：
2022-07-08
期刊：
CIRCULATION RESEARCH
影响因子：
20.1
作者：
Jang, Jihyun;Song, Guang;Pettit, Sarah M.;Li, Qinshan;Song, Xiaosu;Cai, Chen-leng;Kaushal, Sunjay;Li, Deqiang
通讯作者：
Li, Deqiang

Isolation of Embryonic Cardiomyocytes and Cell Proliferation Assay Using Genetically Engineered Reporter Mouse Model.