Dynamic Regulation of Growth Factor Signaling Networks

描述（由申请人提供）：在哺乳动物细胞生物学中，一个持续的挑战是弥合我们在分子、细胞和组织水平上对过程理解的差距。这个生物复杂性层次的中心是信号转导领域，它涉及细胞对外部刺激做出反应的生化机制和途径。该项目的首要目标是将信号转导领域从线性的，以路径为中心的框架移动到以网络为中心的框架;为了做到这一点，我们正在量化反馈调节和串扰相互作用的复杂性，已经证明了我们在阐明成纤维细胞中生长因子受体介导的信号传导的动力学系统特征方面的方法。通过一系列细胞刺激和分子扰动条件的定量实验，以及计算建模，已经全面阐明了由ERK整合的Ras和磷酸肌醇3-激酶（PI 3 K）依赖性信号传导的动态特征，ERK是哺乳动物细胞中最具特征的促分裂原活化蛋白激酶（MAPK）。一些挑战仍然存在，并将在使用分子和计算方法的拟议努力中得到解决：1）将串扰和调节反馈的分子决定因素映射到信号网络的动态特征上; 2）在单细胞水平上探索PI 3 K/Erk信号应答的多样性; 3）受体和细胞系统之间的信号网络的比较分析;和4）阐明携带癌基因的细胞中慢性扰动的信号网络的机制。 公共卫生相关性：该项目的目标是研究特定生化途径之间的复杂相互作用，这些生化途径控制伤口愈合期间的细胞生长和存活，并有助于癌症的进展。通过定量分析这些机制并使用数学模型，我们希望能够预测针对这些途径中分子参与者的干预措施的结果。

DESCRIPTION (provided by applicant): In mammalian cell biology, an ongoing challenge is to bridge the gaps in our understanding of processes at the molecular, cellular, and tissue levels. Central to this hierarchy of biological complexity is the field of signal transduction, which deals with the biochemical mechanisms and pathways by which cells respond to external stimuli. The over-arching goal of this project is to move the signal transduction field from a linear, pathway-centric framework to a network-centric one; to do this; we are quantifying the complexities of feedback regulation and crosstalk interactions, having demonstrated our approach in elucidating dynamical system features of growth factor receptor-mediated signaling in fibroblasts. Quantitative experiments canvassing an array of cell stimulation and molecular perturbation conditions, together with computational modeling, have comprehensively elucidated the dynamic features of Ras- and phosphoinositide 3-kinase (PI3K)-dependent signaling integrated by ERK, the best-characterized mitogen- activated protein kinase (MAPK) in mammalian cells. Certain challenges remain and will be addressed in the proposed effort using molecular and computational approaches: 1) Mapping the molecular determinants of crosstalk and regulatory feedback onto dynamic features of the signaling network; 2) Probing the diversity of PI3K/Erk signaling responses at the single-cell level; 3) Comparative analysis of signaling networks among receptor and cell systems; and 4) Elucidating mechanisms of chronically perturbed signaling networks in cells harboring oncogenes. PUBLIC HEALTH RELEVANCE: The goals of this project are to study the complex interactions between specific biochemical pathways that control cell growth and survival during wound healing and which contribute to the progression of cancer. By analyzing these mechanisms quantitatively and using mathematical models, we hope to be able to predict the outcomes of interventions targeting the molecular players in these pathways.