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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要心力衰竭（HF）是美国死亡的主要原因，通常是由于失去心脏中心肌细胞（CM）。成年哺乳动物CM的增殖潜力非常有限，并且心肌梗塞（MI）和约十亿CM的死亡后，心脏组织受损用纤维化疤痕代替，而不是功能性心肌。已经付出了巨大的努力了解CM在小鼠和内源性心脏模型中的增殖能力再生，但是这些努力并没有导致成功的疗法。在2018年，已显示新生儿猪心具有内源能力，可以在心脏损伤后稳健再生，提供模型有机体其心脏在解剖学和身体上与人心高度相似；因此，调查该模型生物体中的内源性心脏再生具有强大的翻译潜力。因此，该建议是通过表征分子来确定心脏再生的新型热靶标整个产后发育，内源性再生和使用肌膜，全球心脏蛋白质组和全球的新型多图解分析的病理重塑心脏代谢组。 AIM 1使用自上而下的蛋白质组学，这是表征蛋白质成型的主要技术 - 由于遗传变异，替代剪接和后产生的蛋白质产物。翻译修饰 - 广泛表征肉瘤的分子组成拆卸，这是CM增殖过程中发生的过程。这些变化的肌动蛋白变化抽象将与发展，再生和病理重塑的心脏相关，以理解在各种生物状态下的肌节组成。 AIM 2试图表征全球的方式蛋白质组，磷酸蛋白质组和代谢组在产后游泳心脏发育过程中发生了变化，再生和病理重塑，以划定支持再生的分子机制新生儿猪心的能力。这些大型数据集将集成并进行生物信息分析从整体上确定支持猪心肌再生的分子机制。成功的成功这项拟议的工作将阐明开发促进心脏的治疗策略的新目标受伤的人心的再生。