Attractor landscape analysis of the cardiac signaling network reveals mechanism-based therapeutic strategies for heart failure

cardiomyocytes 的 Apoptosis 和肥大是心失败(HF ) 的主要原因，死亡的一个全球带原因，并且通过复杂细胞内部的发信号网络被调整，由于它的复杂性限制有效处理的开发。为了在一个系统为 HF 识别有效治疗学的策略，铺平，我们由集成所有可得到的试验性的证据开发心脏的发信号网络的一个大规模全面数学模型。网络模型的引起注意的人风景分析识别有效地在 ischemic 下面压制 cardiomyocytes 的 apoptosis 和肥大或迫使导致超载的 HF 的控制节点的不同集合， HF 的二种主要类型。有趣地，我们的系统级的分析建议这些控制节点的干预可以为 HF 增加临床的药的功效并且，大多数重要性，控制节点的不同联合作为取决于 HF 的类型的潜在地有效的候选人药目标被建议。我们的学习提供为 HF 开发基于机制的治疗学的策略的一个系统的方法。

Network-based identification of feedback modules that control RhoA activity and cell migration

Cancer cell migration enables metastatic spread causing most cancer deaths.Rho-family GTPases control cell migration,but being embedded in a highly interconnected feedback network,the control of their dynamical behavior during cell migration remains elusive.To address this question,wereconstructed the Rho-family GTPases signaling network involved in cell migration,and developed a Boolean network model to analyze the different states and emergent rewiring of the Rho-family GTPases signaling network at protrusions and during extracellular matrix-dependent cell migration.Extensive simulations and experimental validations revealed that the bursts of RhoA activity induced at protrusions by EGFare regulated by a negative-feedback module composed of Src,FAK,and CSK.Interestingly,perturbing this module interfered with cyclic Rho activation and extracellular matrix-dependent migration,suggesting that CSK inhibition can be a novel and effective intervention strategy for blocking extracellular matrix-dependent cancer cell migration,while Src inhibition might fail,depending on the genetic background of cells.Thus,this study provides new insights into the mechanisms that regulate the intricate activation states of Rho-family GTPases during extracellular matrix-dependent migration,revealing potential new targets for interfering with extracellular matrix-dependent cancer cell migration.