Computational and Experimental Modeling of Cardiomyocyte Proliferation

心肌细胞增殖的计算和实验模型

• 批准号: 10337761
• 负责人: Jeffrey J. Saucerman
• 金额: $ 70.91万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337761
• 关键词: Adult; Algorithms; American; Biological Assay; Biological Models; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiology; Cell Cycle; Cell Differentiation process; Cells; Computer Models; DNA biosynthesis; Data; Development; Experimental Models; Future; Genes; Heart; Heart failure; Hematopoietic; Human; Image; In Vitro; Injury; Literature; Logic; Mammals; Measures; Methodology; Methods; Modeling; Molecular; Molecular Biology; Mus; Myocardium; Natural regeneration; Neonatal; Network-based; Organ; Outcome; Pathway interactions; Phenotype; Prevalence; Proteins; Regulation; Reproducibility; Signal Transduction; System; Testing; Therapeutic; Transforming Growth Factor alpha; Transforming Growth Factor beta; Validation; Work; base; cardiac regeneration; cell regeneration; experience; experimental study; gene discovery; genome-wide; in vivo; in vivo regeneration; induced pluripotent stem cell derived cardiomyocytes; innovation; insight; knock-down; live cell microscopy; molecular modeling; mouse model; network models; novel; organ regeneration; postnatal development; predictive modeling; prenatal; regeneration potential; regenerative; regenerative therapy; screening; skeletal; stem cell differentiation; stem cells; therapeutic candidate; therapeutic target

Summary Heart failure arises in large part due to the very limited ability of cardiomyocytes to regenerate following injury. Recent studies have identified some molecular regulators of cardiomyocyte proliferation in mammals, but the field lacks an understanding of how these and yet-to-be identified components work as a system to regulate cardiomyocyte proliferation. A better understanding of the pathways that control CM proliferation and cell cycle exit is needed in order to develop strategies that stimulate CM proliferation as a regenerative therapy. Here, we integrate innovative computational and experimental methods to develop a systems-level understanding of cardiomyocyte proliferation. First, we develop a literature-based computational model of the molecular network, comprising known regulators of cardiomyocyte proliferation. This network model is expanded mechanistically to include novel regulators of cardiomyocyte proliferation that we have discovered through a genome-wide phenotypic screen, including several in a TGF-beta module. Model-predicted regulators within this TGF-beta module are validated experimentally in mouse cardiomyocytes, human induced pluripotent stem-cell derived cardiomyocytes, and an in vivo mouse model of cardiac regeneration. Overall, this study will provide novel candidate therapeutic targets for cardiomyocyte proliferation, the first mechanistic model integrating these candidates and known regulators of cardiomyocyte proliferation, and experimental validation that the model can predict network perturbations that enhance cardiomyocyte proliferation in vitro and in vivo.

摘要 心力衰竭在很大程度上是由于心肌细胞在损伤后再生的能力非常有限。 最近的研究已经确定了一些哺乳动物心肌细胞增殖的分子调控因素，但 菲尔德缺乏对这些尚未确定的组件如何作为一个系统进行监管的理解 心肌细胞增殖。更好地了解控制CM增殖和细胞周期的途径 需要退出，以制定刺激CM增殖的战略，作为一种再生疗法。在这里，我们 整合创新的计算和实验方法，以形成对 心肌细胞增殖。首先，我们开发了一个基于文献的分子网络计算模型， 由已知的心肌细胞增殖调节剂组成。这种网络模型是机械地扩展的 包括我们通过全基因组发现的心肌细胞增殖的新调节因子 表型筛选，包括几个在转化生长因子-β模块。模型预测的这一转化生长因子-β内的调节因子 模块在小鼠心肌细胞、人诱导的多能干细胞来源的实验中得到验证 心肌细胞，以及心脏再生的活体小鼠模型。总体而言，这项研究将提供新颖的 心肌细胞增殖的候选治疗靶点，第一个整合这些靶点的机制模型 候选和已知的心肌细胞增殖调节因子，并通过实验验证该模型 可以预测在体外和体内促进心肌细胞增殖的网络扰动。