Elucidating the endocrine regulation of cardiac regeneration in vertebrates

阐明脊椎动物心脏再生的内分泌调节

• 批准号: 10172968
• 负责人: Stephen Cutie
• 金额: $ 1.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172968
• 关键词: Adult; Animals; Apical; Automobile Driving; Cardiac; Cardiac Myocytes; Cause of Death; Cell Cycle; Cells; Cessation of life; Cytokinesis; DNA biosynthesis; Development; Diploidy; Echocardiography; Endocrine; Evolution; Excision; Exhibits; Fibrosis; Heart; Heart Diseases; Heart Injuries; Heterocephalus; Histologic; Human; In Vitro; Mammals; Metabolism; Mole Rats; Molecular; Mononuclear; Mus; Myocardial Infarction; Neonatal; Ontology; Organ; Patients; Phylogenetic Analysis; Physiological; Ploidies; Polyploidy; Proliferating; Regenerative capacity; Regenerative pathway; Regulation; Reptiles; Serum; System; Tamoxifen; Testing; Thyroid Hormones; United States; Vertebrates; Withdrawal; Zebrafish; cardiac regeneration; hormonal signals; in vivo; insight; ischemic injury; metabolic rate; neonatal human; neonatal mice; neonate; novel; novel therapeutic intervention; novel therapeutics; regeneration potential; regenerative; trait

ABSTRACT Organ regenerative potential varies ontologically and phylogenetically. While lower vertebrates and neonatal mammals retain robust capacities for heart regeneration, adult mammals generally resolve cardiac injury through fibrosis, not regeneration. However, the underlying mechanisms driving loss of such a seemingly advantageous trait in evolution and development remain enigmatic. Mammalian hearts lose regenerative potential due to cardiomyocyte cell-cycle withdrawal and polyploidization. Using cardiomyocyte ploidy as an indicator of regenerative potential, we screened 23 mammalian species and identified the Naked-Mole Rat (NMR), Heterocephalus glaber, as having an unusually high diploid cardiomyocyte percentage. We uncovered a robust correlation between cardiomyocyte ploidy and standard metabolism, a physiological parameter primarily regulated by thyroid hormone (TH). Serum TH in NMRs is unusually low for a mammal, and preliminary evidence suggests NMR cardiomyocytes can proliferate. Additionally, we have observed that TH inhibition enhances mouse cardiomyocyte proliferation and reduces ploidy, while exogenous TH inhibits cardiomyocyte proliferation in zebrafish. Thus, we hypothesize that NMRs possess enhanced cardiac regenerative potential and that the distinct TH levels in NMRs, mice, and zebrafish contribute to their distinct cardiac regenerative potentials. Our Aim #1 will assess NMR cardiac regenerative potential in vitro and in vivo. Aim #2 will determine if TH inhibition enhances cardiac regeneration in adult mice. Aim #3 will test whether exogenous TH inhibits cardiac regeneration in zebrafish. Studying the influence of TH over cardiac regeneration could yield novel insights into the molecular control of organ regenerative potential in development and evolution.

抽象的 器官再生潜力在本体论和系统发育上有所不同。虽然低等脊椎动物和 新生哺乳动物保留了强大的心脏再生能力，成年哺乳动物通常会解决 心脏损伤是通过纤维化而非再生造成的。然而，导致损失的根本机制 这种在进化和发展中看似有利的特征仍然是个谜。哺乳动物心脏 由于心肌细胞细胞周期退出和多倍化而失去再生潜力。使用 心肌细胞倍性作为再生潜力的指标，我们筛选了 23 个哺乳动物物种并 鉴定出裸鼹鼠 (NMR) Heterocephalus glaber 具有异常高的二倍体 心肌细胞百分比。我们发现心肌细胞倍性和 标准代谢，主要由甲状腺激素（TH）调节的生理参数。血清 对于哺乳动物来说，NMR 中的 TH 异常低，初步证据表明 NMR 心肌细胞 可以增殖。此外，我们观察到 TH 抑制可增强小鼠心肌细胞 增殖并降低倍性，而外源 TH 抑制斑马鱼心肌细胞增殖。 因此，我们假设 NMR 具有增强的心脏再生潜力，并且不同的 NMR、小鼠和斑马鱼的 TH 水平有助于其独特的心脏再生 潜力。我们的目标#1 将评估 NMR 心脏再生潜力的体外和体内。目的 #2 将确定 TH 抑制是否会增强成年小鼠的心脏再生。目标 #3 将测试是否 外源性 TH 抑制斑马鱼心脏再生。研究 TH 对心脏的影响 再生可以对器官再生潜力的分子控制产生新的见解 发展和演变。