Cardiac regeneration by histone deacetylases

组蛋白脱乙酰酶促进心脏再生

• 批准号: 10773731
• 负责人: Deqiang Li
• 金额: $ 22.85万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 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/10773731
• 关键词: Cardiac; regeneration; histone; deacetylases

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和死亡的主要原因。成人 哺乳动物心脏的再生潜力有限。刺激措施等多项措施 通过激活细胞周期来诱导预先存在的心肌细胞增殖，之前已尝试诱导 心脏再生，尽管迄今为止只取得了有限的效果。成年心肌细胞需要 如果不同时的话，在增殖之前首先经历去分化。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相关，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心肌细胞 增殖能力，或者利用成年心肌细胞的表观遗传学是否刺激增殖。 通过对小鼠胚胎日（E）14.5心脏（增殖 活跃）和成人心脏（增殖惰性），我们确定了许多染色质重塑因子 包括组蛋白脱乙酰酶 7 (HDAC7)，其在 E14.5 心脏中富集，但在成人心脏中缺失。 HDAC7属于II类HDAC，具有特定的组织分布并在组织之间穿梭。 细胞核和细胞质对信号作出反应。研究表明，HDAC7 的敲除会损害 HDAC7 的过度表达会诱导肿瘤生长并影响心脏发育过程中的血管完整性。 上皮增殖。然而，HDAC7 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除 HDAC7 后 （NMCM），我们发现心肌细胞增殖显着下降。相比之下， NMCM 中 HDAC7 的过度表达导致显着的心肌细胞去分化并增加 增殖。此外，体内成人心肌细胞中 HDAC7 的过度表达显着诱导 心肌梗塞后心肌细胞增殖并改善心功能。根据这些小说 和令人兴奋的初步发现，我们假设 HDAC7 对于心肌细胞来说是必需的 增殖并足以重新激活出生后心肌细胞的增殖和再生 潜力。提出了三个目标来检验我们的中心假设。目标 1：确定机制 HDAC7通过HDAC7促进心肌细胞增殖；目标 2：确定 HDAC7 是否是必需的 心肌细胞增殖；目标3：测试HDAC7过度表达是否促进成年心肌细胞 增殖并改善心肌损伤后的心脏功能。我们打算通过以下方式实现这些目标 采用小鼠遗传学、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颖且严格的治疗策略来促进心脏 再生并为人类有效修复心脏铺平一条新途径。