Regulation of cardiac myocyte proliferation and myocardial regeneration in Ciona

描述(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，这导致心肌的结构和功能缺陷。为了开发针对性很好的治疗策略，以纠正儿童或成人患者的心脏病，必须明确指导心肌细胞增殖的调控程序。脊椎动物模型系统经常被用来剖析调节发育和疾病过程的分子机制。然而，肠道乔纳是一种无脊椎动物模型系统，具有很好的特点，在心脏发育研究中具有许多优势，包括：保守的心脏基因网络，相对简单的心脏设计，减少遗传冗余，以及相对容易地研究大种群的能力。尽管它很简单，但Ciona的心脏发育类似于早期脊椎动物的胚胎，并为研究调节发育的信号通路提供了一条直接的途径，而高等生物体中的信号通路极其复杂。哺乳动物心脏和Ciona心脏的一个显著区别是Ciona能够在其整个生命周期内再生心肌细胞，这使得Ciona心肌细胞增殖的调控机制非常耐人寻味。引导心肌细胞增殖的信号机制尚未被研究过。这项建议的目的是确定在原始脊索动物的单纯心脏中调节心肌细胞增殖和心肌再生的信号机制。主要目标是首先确定已知的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Ciona的心脏发育。其次，将研究Ciona心脏的再生特性，并将利用现代分子技术识别涉及的信号机制。了解心肌细胞增殖和心肌再生的调控机制将有助于简化人类心脏发育的复杂调控网络的阐明，从而促进心血管疾病治疗新策略的发展。 公共卫生相关性：这项拟议的研究旨在了解原始脊索动物--肠黄牛的心肌细胞增殖和心肌再生的调节机制。哺乳动物心肌细胞在出生后不会增殖，而乔纳心脏中的心肌细胞在整个生命过程中可以再生，两者之间的分子差异尚不清楚。在心脏病患者实施诱导心肌细胞增殖的策略之前，有必要完全了解心肌细胞的细胞周期调节。这些拟议的研究将为阐明控制心肌细胞增殖和心肌再生的调控网络提供所需的信息，这将对开发针对心脏病治疗的靶向性良好的治疗策略和有效的药物治疗具有深远的意义。

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.