Regulation of cardiac myocyte proliferation and myocardial regeneration in Ciona

海鞘心肌细胞增殖和心肌再生的调控

• 批准号: 7980712
• 负责人: Heather J. Evans-Anderson
• 金额: $ 41.73万
• 依托单位: WINTHROP UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7980712
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; Adolescent; Adult; Affect; Animal Model; Biological Models; Bromodeoxyuridine; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Cycle Regulation; Cell Proliferation; Cells; Childhood; Chordata; Ciona intestinalis; Complex; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Disease; Embryo; Employee Strikes; Genes; Genetic; Goals; Growth Factor; Health; Heart; Heart Diseases; Human; Hypoxia; In Situ Hybridization; Injection of therapeutic agent; Injury; Invertebrates; Life; Longevity; Maintenance; Marines; Mediating; Microarray Analysis; Molecular; Myocardial; Myocardium; Natural regeneration; Organism; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Process; Proliferating; Proliferation Marker; Property; Regulation; Relative (related person); Research; Rest; Signal Pathway; Signal Transduction; Signaling Molecule; South Carolina; Specimen; Staging; Techniques; Transgenic Organisms; United States; Vertebrates; cardiogenesis; congenital heart disorder; design; infant death; mortality; novel; novel therapeutics; programs; public health relevance; regenerative; therapeutic development; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Congenital heart disorders are the most prevalent lethal birth defects and cardiovascular disease is the leading cause of mortality in adults. A common feature in both pediatric and adult heart disease is altered regulation of cardiac myocyte proliferation, which leads to structural and functional defects in the myocardium. In order to develop well-targeted therapeutic strategies designed to correct heart disease in pediatric or adult patients, the regulatory program directing cardiac myocyte proliferation must be well defined. Vertebrate animal model systems are often used to dissect the molecular mechanisms that regulate developmental and disease processes. However, Ciona intestinalis is an invertebrate animal model system that is well characterized and has many advantages for the study of heart development including: a conserved cardiac gene network, a relatively simple heart design, reduced genetic redundancy, and the ability to study large populations with relative ease in maintenance of the colony. Despite its simplicity, heart development in Ciona is similar to early vertebrate embryos and provides a straightforward avenue for the study of signaling pathways that regulate development, which are extremely complex in higher organisms. A striking difference between mammalian hearts and the Ciona heart is that Ciona are capable of regenerating cardiac myocytes throughout its lifespan, which makes the regulatory mechanisms of cardiac myocyte proliferation in Ciona very intriguing. The signaling mechanisms directing cardiac myocyte proliferation in the Ciona heart have not yet been studied. The goal of this proposal is to determine the signaling mechanisms that regulate cardiac myocyte proliferation and myocardial regeneration in the simple heart of the primitive chordate, Ciona intestinalis. The primary objective is to first determine if transcription factors and signaling molecules known to affect cardiac myocyte proliferation in vertebrates are involved in regulating heart development in Ciona using a transgenic approach. Secondly, the regenerative properties of the Ciona heart will be studied and the signaling mechanisms involved will be identified using modern molecular techniques. Understanding the regulatory mechanisms of cardiac myocyte proliferation and myocardial regeneration in Ciona intestinalis would help simplify the elucidation of the complex regulatory networks directing heart development in humans, which would promote the development of new therapeutic strategies to treat cardiovascular disease. PUBLIC HEALTH RELEVANCE: The proposed research aims to understand the regulatory mechanisms of cardiac myocyte proliferation and myocardial regeneration in the primitive chordate, Ciona intestinalis. The molecular differences between mammalian cardiac myocytes that do not proliferate post-natally and cardiac myocytes in the Ciona heart that are regenerative throughout life are unknown. A complete understanding of cell cycle regulation in cardiac myocytes is necessary before strategies to induce proliferation in these cells can be implemented for patients suffering from cardiac disease. The proposed studies will provide information needed to elucidate the regulatory networks controlling cardiac myocyte proliferation and myocardial regeneration in Ciona, which will have profound implications in the development of well targeted therapeutic strategies and effective drug therapies directed toward the treatment of cardiac disease.

描述（由申请人提供）：先天性心脏病是最常见的致命出生缺陷，心血管疾病是成人死亡的主要原因。儿童和成人心脏病的一个共同特征是心肌细胞增殖调节的改变，从而导致心肌的结构和功能缺陷。为了制定旨在纠正儿科或成人患者心脏病的针对性良好的治疗策略，必须明确定义指导心肌细胞增殖的调节程序。脊椎动物模型系统通常用于剖析调节发育和疾病过程的分子机制。然而，海鞘是一种无脊椎动物模型系统，具有良好的特征，对于心脏发育的研究具有许多优点，包括：保守的心脏基因网络、相对简单的心脏设计、减少的遗传冗余以及研究大群体的能力。蜂群的维护相对容易。尽管很简单，海鞘的心脏发育与早期脊椎动物胚胎相似，并为研究调节发育的信号通路提供了直接的途径，而这些信号通路在高等生物中极其复杂。哺乳动物心脏与玻璃海鞘心脏的一个显着区别是玻璃海鞘在其整个生命周期中都能够再生心肌细胞，这使得玻璃海鞘心肌细胞增殖的调节机制非常有趣。尚未研究玻璃海鞘心脏中指导心肌细胞增殖的信号机制。该提案的目标是确定原始脊索动物玻璃海鞘的简单心脏中调节心肌细胞增殖和心肌再生的信号传导机制。主要目标是首先确定已知影响脊椎动物心肌细胞增殖的转录因子和信号分子是否参与使用转基因方法调节玻璃海鞘的心脏发育。其次，将研究玻璃海鞘心脏的再生特性，并利用现代分子技术确定所涉及的信号传导机制。了解玻璃海鞘心肌细胞增殖和心肌再生的调节机制将有助于简化阐明指导人类心脏发育的复杂调节网络，从而促进治疗心血管疾病的新治疗策略的开发。 公共健康相关性：本研究旨在了解原始脊索动物海鞘心肌细胞增殖和心肌再生的调节机制。出生后不增殖的哺乳动物心肌细胞与终生再生的玻璃海鞘心脏中的心肌细胞之间的分子差异尚不清楚。在对患有心脏病的患者实施诱导这些细胞增殖的策略之前，必须全面了解心肌细胞的细胞周期调节。拟议的研究将提供阐明控制 Ciona 心肌细胞增殖和心肌再生的调控网络所需的信息，这将对开发针对性强的治疗策略和针对心脏病治疗的有效药物疗法产生深远的影响。