A Novel Multiomics-based Systems Biology Approach to Understanding Cardiac Regeneration in Swine

项目摘要 心力衰竭（HF）是美国的主要死亡原因，并且通常是由心功能丧失引起的。 心肌细胞（CM）群体。成年哺乳动物CM具有非常有限的增殖潜力， 在心肌梗塞（MI）和大约10亿CM死亡之后， 取而代之的是纤维化疤痕而不是功能正常的心肌。已作出重大努力， 了解CM在内源性心脏病小鼠和斑马鱼模型中的增殖能力， 再生，但这些努力并没有导致成功的治疗。2018年，研究表明，新生儿 猪心脏在心脏损伤后具有强大的内源性再生能力，提供了一种模式生物 其心脏在解剖学和生理学上与人类心脏高度相似;因此，研究 该模式生物体中的内源性心脏再生具有强的翻译潜力。因此， 该建议是通过表征心脏再生的分子， 新生猪心脏在整个出生后发育、内源性再生和 使用肌节、全局心脏蛋白质组和全局蛋白质组的新的多组学分析， 心脏代谢组Aim 1使用自上而下的蛋白质组学，这是表征蛋白质型的首要技术-所有 由单个基因产生的蛋白质产物是遗传变异、选择性剪接和后剪接的结果。 翻译修饰-广泛表征肌节的分子组成， 分解，这是CM增殖过程中发生的一个过程。这些肌节蛋白形式的变化 丰度将与心脏的发育、再生和病理性重塑相关， 在各种生物状态下的肌节组成。目标2旨在描述全球 蛋白质组、磷酸化蛋白质组和代谢组在出生后猪心发育过程中发生变化， 再生和病理性重塑，以描绘支持再生的分子机制。 新生猪心的容量。这些大型组学数据集将被整合并进行生物信息学分析。 全面鉴定支持猪心肌再生的分子机制。的成功 这项拟议的工作将阐明新的目标，为发展治疗策略，以促进心脏 修复受伤的心脏

PROJECT SUMMARY Heart failure (HF) is a leading cause of death in the United States and is often caused by the loss of cardiomyocyte (CM) populations in the heart. Adult mammalian CMs have very limited proliferative potential, and after myocardial infarction (MI) and the death of approximately one billion CMs, damaged cardiac tissue is replaced with fibrotic scar rather than with functioning myocardium. Significant efforts have been made to understand the proliferative capacity of CMs in mouse and zebrafish models of endogenous cardiac regeneration, but these efforts have not led to successful therapies. In 2018, it was shown that the neonatal swine heart has an endogenous capacity to robustly regenerate after cardiac injury, providing a model organism whose heart is anatomically and physiologically highly similar to the human heart; therefore, investigating endogenous cardiac regeneration in this model organism has strong translational potential. As such, the goal of this proposal is to identify novel therapeutic targets for cardiac regeneration by characterizing the molecular landscape of the neonatal swine heart throughout postnatal development, endogenous regeneration, and pathological remodeling using a novel multiomics analysis of the sarcomere, global cardiac proteome, and global cardiac metabolome. Aim 1 uses top-down proteomics, the premier technology to characterize proteoforms – all the protein products that arise from a single gene as a result of genetic variations, alternative splicing, and post- translational modifications – to extensively characterize the molecular composition of sarcomeres that can disassemble, a process that occurs during CM proliferation. These changes in sarcomere proteoform abundances will be correlated to developing, regenerating, and pathologically remodeling hearts to understand the sarcomere composition during various biological states. Aim 2 seeks to characterize how the global proteome, phosphoproteome, and metabolome are altered throughout postnatal swine heart development, regeneration, and pathological remodeling to delineate molecular mechanisms that support the regenerative capacity of neonatal swine hearts. These large -omics data sets will be integrated and bioinformatically analyzed to holistically identify the molecular mechanisms that support myocardial regeneration in swine. The success of this proposed work will elucidate novel targets for developing therapeutic strategies to promote cardiac regeneration in the injured human heart.