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

一种基于多组学的新型系统生物学方法来了解猪的心脏再生

• 批准号: 10599610
• 负责人: Timothy Aballo
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599610
• 关键词: Adult; Affect; Alabama; Alternative Splicing; Anatomy; Anterior Descending Coronary Artery; Bioinformatics; Biological; Biological Models; Birth; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Cycle Arrest; Cessation of life; Cicatrix; Collaborations; Consultations; Data Set; Development; EFRAC; Family suidae; Functional disorder; Genes; Genetic Variation; Glycolysis; Goals; Harvest; Heart; Heart Injuries; Heart failure; Human; Immunofluorescence Immunologic; Infarction; Injury; Left; Ligation; Mass Spectrum Analysis; Measurement; Mediating; Metabolic; Metabolism; Modeling; Molecular; Molecular Profiling; Morphology; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; PIK3CG gene; Pathologic; Physiological; Physiology; Population; Post-Translational Protein Processing; Prevalence; Process; Proliferating; Proteins; Proteome; Proteomics; Proto-Oncogene Proteins c-akt; Regenerative capacity; Regenerative response; Regulatory Pathway; Research; Sarcomeres; Signal Transduction; Structure; Systems Biology; Techniques; Technology; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; United States; Universities; Work; Zebrafish; cardiac regeneration; cardiogenesis; curative treatments; design; fascinate; fatty acid oxidation; fetal; heart damage; injured; insight; metabolome; metabolomics; model organism; multiple omics; neonatal mice; new therapeutic target; novel; phosphoproteomics; porcine model; postnatal; postnatal development; postnatal period; prevent; protein expression; regeneration potential; regenerative; response; success; targeted treatment; tool; translational potential; ultra high resolution

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.

项目概要 心力衰竭 (HF) 是美国的一个主要原因，通常是由于心脏功能丧失造成的 心脏中的心肌细胞 (CM) 群体。成年哺乳动物 CM 的增殖潜力非常有限，并且 心肌梗死 (MI) 和约 10 亿 CM​​ 死亡后，受损的心脏组织 被纤维化疤痕而不是功能正常的心肌所取代。已做出重大努力 了解 CM 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。 2018年，有研究表明，新生儿 猪心脏具有心脏损伤后强劲再生的内源能力，提供了模型生物体 心脏在解剖学和生理学上与人类心脏高度相似；因此，调查 该模型生物体的内源性心脏再生具有强大的转化潜力。因此，目标是 该提案旨在通过表征分子特征来确定心脏再生的新治疗靶点 新生猪心脏在整个产后发育、内源再生和 使用肌节、整体心脏蛋白质组和整体的新型多组学分析进行病理重塑 心脏代谢组。目标 1 使用自上而下的蛋白质组学，这是表征蛋白质形式的首要技术 – 所有 由于遗传变异、选择性剪接和后处理而由单个基因产生的蛋白质产物 翻译修饰——广泛表征肌节的分子组成，可以 分解，CM 增殖过程中发生的过程。肌节蛋白质的这些变化 丰度将与心脏的发育、再生和病理重塑相关，以了解 各种生物状态下的肌节组成。目标 2 旨在描述全球如何 蛋白质组、磷酸蛋白质组和代谢组在猪产后心脏发育过程中发生变化， 再生和病理重塑来描述支持再生的分子机制 新生猪心脏容量。这些大型组学数据集将被整合并进行生物信息分析 全面确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开发治疗策略以促进心脏功能的新目标 受伤的人类心脏的再生。