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

项目总结 心力衰竭(HF)在美国是主要的死亡原因，通常是由心脏功能丧失引起的 心脏中的心肌细胞(CM)群。成年哺乳动物CMS的增殖潜力非常有限，而且 在心肌梗死(MI)和大约10亿CMS死亡后，受损的心脏组织 取而代之的是纤维性瘢痕，而不是功能心肌。已经做出了重大努力，以 了解CMS在小鼠和斑马鱼内源性心脏模型中的增殖能力 再生，但这些努力并没有带来成功的治疗方法。2018年，有数据显示，新生儿 猪心脏在心脏损伤后具有强大的再生能力，提供了一个模式生物 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 这种模式生物的内源性心脏再生具有很强的翻译潜力。因此，目标是 这项提议是通过表征分子来确定心脏再生的新的治疗靶点 新生猪心脏在出生后发育、内源性再生和 用一种新的肌节、整体心肌蛋白质组和整体蛋白质组多组学分析进行病理重塑 心脏代谢体。AIM 1使用自上而下的蛋白质组学，这是表征蛋白质形式-ALL的首要技术 单个基因由于遗传变异、选择性剪接和后剪接而产生的蛋白质产物。 翻译修饰-广泛表征肌节的分子组成，可以 分解，这是在CM增殖过程中发生的一个过程。这些肌节蛋白形式的变化 丰度将与心脏发育、再生和病理性重塑相关，以了解 各种生物状态下的肌节组成。目标2试图刻画全球经济如何 蛋白质组、磷蛋白质组和代谢组在生后猪心脏发育过程中都会发生变化， 再生和病理重塑，以描绘支持再生的分子机制 新生猪心容量。这些大型组学数据集将被整合并进行生物信息分析 全面鉴定支持猪心肌再生的分子机制。的成功之处 这项拟议的工作将阐明开发治疗策略以促进心脏疾病的新靶点 在受伤的人类心脏中再生。

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.