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.

总结 心力衰竭的发生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哺乳动物心肌细胞增殖的一些分子调节因子，但 该领域缺乏对这些和尚未确定的组件如何作为一个系统进行调节的理解 心肌细胞增殖更好地了解控制CM增殖和细胞周期的途径 为了开发刺激CM增殖作为再生疗法的策略，需要退出。这里我们 整合创新计算和实验方法，以发展系统级的理解 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， 包括已知的心肌细胞增殖调节剂。这个网络模型是机械地扩展的 包括我们通过全基因组研究发现的心肌细胞增殖的新调节因子， 表型筛选，包括TGF-β模块中的几个。模型预测的TGF-β调节因子 模块在小鼠心肌细胞、人诱导多能干细胞衍生的 心肌细胞和心脏再生的体内小鼠模型。总的来说，这项研究将提供新的 心肌细胞增殖的候选治疗靶点，第一个整合这些机制的模型， 候选人和已知的心肌细胞增殖的调节剂，以及实验验证，该模型 可以预测在体外和体内增强心肌细胞增殖的网络扰动。