Quantification of the decline of heart muscle cell proliferation and its reversal in pediatric patients

儿科患者心肌细胞增殖下降及其逆转的量化

• 批准号: 10413070
• 负责人: Bernhard Kuhn
• 金额: $ 41.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413070
• 关键词: Affect; Age; Anatomy; Biology; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Cycle Arrest; Cell Proliferation; Cell division; Cells; Child; Childhood; Clinical; Clinical Research; Congenital Abnormality; DNA; Data; Development; Diagnosis; Dilated Cardiomyopathy; Disease; Elements; Enrollment; Excision; Funding; Gastrointestinal tract structure; Heart; Heart Diseases; Heart Transplantation; Heart failure; Human; Human body; Infant; Institutional Review Boards; Isotopes; Label; Life; Measures; Mechanics; Medicine; Methods; Morbidity - disease rate; Myocardium; Natural regeneration; Neonatal; Newborn Infant; Observational Study; Obstruction; Operative Surgical Procedures; Organ; Pathologist; Patients; Pattern; Population; Prevention; Proliferating; Protocols documentation; Publishing; Research; Research Design; Resected; Right ventricular structure; S phase; Scientist; Skin; Surgeon; Testing; Tetralogy of Fallot; Thymidine; Time; Tissue Sample; Tissues; Transplantation; Ventricular; Withdrawal; Workload; age group; cardiac regeneration; cardiogenesis; cell regeneration; congenital heart disorder; experience; first-in-human; improved; innovation; left ventricular assist device; mass spectrometric imaging; mechanical circulatory support; mortality; muscle regeneration; neonate; novel therapeutics; offspring; pediatric cardiologist; pediatric patients; premature; prevent; prospective; regenerative approach; regenerative therapy; repaired; stable isotope

ABSTRACT: Heart failure continues to be a leading cause of mortality and morbidity. Understanding the basic mechanisms of heart regeneration in humans and stimulating them would improve the lives of many patients. Proliferation of heart muscle cells (cardiomyocytes) is essential for heart development and regeneration. After birth, the proliferative potential of cardiomyocytes declines, but neonatal mammalian hearts are thought to maintain the ability to regenerate until cardiomyocytes undergo permanent cell cycle arrest, establishing a barrier for regeneration. Strategies for stimulating cardiomyocyte proliferation are under development and would be most effective when initiated before cardiomyocytes withdraw permanently from the cell cycle. However, the point at which cardiomyocyte proliferation ceases in humans is controversial; some studies place this point before birth, some in the first year after birth, and our data demonstrate cardiomyocyte proliferation extending well into childhood, i.e., the first 10 – 20 years of life. This picture is further complicated by our published and unpublished results suggesting that infants with congenital heart disease (CHD) have decreased cardiomyocyte proliferation. Resolving how age and heart disease alter the temporal pattern of cardiomyocyte cell cycle withdrawal is an essential problem in cardiac biology. Improved understanding of cardiomyocyte proliferation will be critical for developing new regenerative strategies to prevent and treat heart failure in patients with cyanotic CHD, the most common birth defect affecting 0.3% of newborns. We will determine when cardiomyocyte proliferation decreases in pediatric patients by investigating two leading cardiac diseases: tetralogy of Fallot (ToF), the most common form of cyanotic congenital heart disease (CHD), which affects 0.3% of newborns, and dilated cardiomyopathy (DCM), the most common cause for heart transplantation in the pediatric age group. Our central hypothesis is that cardiomyocyte proliferation shows an age- and disease-dependent decline. We will enroll neonates, infants, and children to quantify cardiomyocyte proliferation. We have formed a research team consisting of pediatric cardiologists and cardiac surgeons, pathologists, and basic scientists. The critical element of our approach is the use of a highly innovative method in which we will label patients with innocuous thymidine carrying stable isotope markers (15N-thymidine and 2H- thymidine). Cells in S-phase of the cell cycle incorporate thymidine into their DNA, and their offspring retain the label for at least 6 cell divisions. We will visualize the isotope in post-surgical tissue samples with an innovative method: Multi-isotope imaging mass spectrometry (MIMS) to quantify cardiomyocyte proliferation and differentiation. Preliminary data from our first study patient with ToF provide first-in-human results and validate our approach.

抽象的： 心力衰竭仍然是死亡率和发病率的主要原因。了解基本机制 人类的心脏再生并刺激它们会改善许多患者的生活。增殖 心肌细胞（心肌细胞）对于心脏发育和再生至关重要。出生后 心肌细胞的增殖潜力下降，但新生儿哺乳动物的心被认为维持 能够再生直到心肌细胞经历永久性细胞周期停滞，建立了一个障碍 再生。刺激心肌细胞增殖的策略正在开发中，将是大多数 在心肌细胞从细胞周期永久退出之前启动时有效。但是，这是 人类中哪些心肌细胞增殖停止是有争议的。一些研究在出生前就将这一点放在 一些在出生后的第一年，我们的数据表明心肌细胞的增殖延伸到 童年，即生命的前10 - 20年。这张图片使我们发表的发表更加复杂， 未发表的结果表明，先天性心脏病（CHD）的婴儿有所改善 心肌细胞增殖。解决年龄和心脏病如何改变心肌细胞的临时模式 细胞周期提取是心脏生物学中的重要问题。改善对心肌细胞的了解 扩散对于制定新的再生策略至关重要，以预防和治疗心力衰竭 氰基冠心病患者，最常见的先天缺陷影响了0.3％的新生儿。我们将确定 当儿科患者通过研究两种主要心脏病而减少心肌细胞增殖时： Fallot（TOF）的四边形，这是蓝毒先天性心脏病（CHD）的最常见形式，它影响 0.3％的新生儿和扩张的心肌病（DCM），这是心脏移植的最常见原因 小儿年龄段。我们的中心假设是心肌细胞增殖显示了年龄和年龄 疾病依赖性下降。我们将注册新生儿，婴儿和儿童以量化心肌细胞 增殖。我们组成了一个由儿科心脏病专家和心脏外科医生组成的研究团队， 我们方法的关键要素是使用高度创新的方法 在其中，我们将标记携带稳定同位素标记（15n-胸腺定和2H-）的无害胸苷患者 胸苷）。细胞周期S期的细胞将胸苷掺入其DNA中，其后代保留 标记至少6个单元格。我们将在具有创新性的手术后组织样品中可视化同位素 方法：多同位素成像质谱法（MIMS），以量化心肌细胞增殖和 分化。我们的第一个研究患者的初步数据可提供首次人类的结果和 验证我们的方法。