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:
    10197217
  • 负责人:
  • 金额:
    $ 37.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2025-06-30
  • 项目状态:
    未结题

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球发病率和死亡率的主要原因。成人 哺乳动物心脏显示出有限的再生潜力。许多措施,如刺激 先前已经尝试通过激活细胞周期来诱导预先存在的心肌细胞增殖, 心脏再生,尽管迄今为止只取得了适度的效果。成年心肌细胞需要 在增殖之前首先经历去分化,如果不是同时的话。事实上,成年斑马鱼的心脏 再生通过去分化和增殖完成。染色质状态和 重塑通常与许多生理或病理过程相关, 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14.5天(E)心脏(增殖)的比较转录组学分析, 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 包括在E14.5心脏中富集但在成人心脏中缺失的组蛋白脱乙酰酶7(HDAC 7)。 HDAC 7属于II类HDAC,其具有特定的组织分布,并且穿梭于细胞之间。 细胞核和细胞质对信号的反应。研究表明,敲除HDAC 7会损害 心脏发育过程中的血管完整性,而HDAC 7的过表达诱导肿瘤生长, 上皮增生然而,HDAC 7在心肌细胞增殖中的潜在作用尚未确定。 在我们的初步研究中,在培养的新生小鼠心肌细胞中敲低HDAC 7后, (NMCMs),我们发现心肌细胞增殖显著降低。相比之下, HDAC 7在NMCMs中的过表达导致显著的心肌细胞去分化, 增殖此外,HDAC 7在体内成年心肌细胞中的过表达显著诱导了心肌细胞的凋亡。 心肌细胞增殖和改善心肌梗死后的心功能。根据这些小说 和令人兴奋的初步发现,我们假设HDAC 7是心肌细胞所必需的, 增殖和足以重新激活出生后心肌细胞增殖和再生 潜力提出了三个目标来检验我们的中心假设。目标1:确定机制 HDAC 7通过其促进心肌细胞增殖;目的2:确定HDAC 7是否是心肌细胞增殖所必需的。 目的3:测试HDAC 7过表达是否促进成年心肌细胞增殖; 增殖和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个新的和严格的治疗策略,促进心脏 再生,并为人类有效的心脏修复铺平了新的道路。

项目成果

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Deqiang Li其他文献

Deqiang Li的其他文献

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{{ truncateString('Deqiang Li', 18)}}的其他基金

Cardiac regeneration by histone deacetylases
组蛋白脱乙酰酶促进心脏再生
  • 批准号:
    10773731
  • 财政年份:
    2022
  • 资助金额:
    $ 37.04万
  • 项目类别:
Cardiac regeneration by histone deacetylases
组蛋白脱乙酰酶促进心脏再生
  • 批准号:
    10700815
  • 财政年份:
    2022
  • 资助金额:
    $ 37.04万
  • 项目类别:
Cardiac regeneration by histone deacetylases
组蛋白脱乙酰酶促进心脏再生
  • 批准号:
    10439468
  • 财政年份:
    2020
  • 资助金额:
    $ 37.04万
  • 项目类别:
Cardiac regeneration by histone deacetylases
组蛋白脱乙酰酶促进心脏再生
  • 批准号:
    10027359
  • 财政年份:
    2020
  • 资助金额:
    $ 37.04万
  • 项目类别:

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