Defining Signal Network Plasticity

描述(由申请人提供)：信号网络的可塑性允许细胞响应根据不同的环境条件而变化。有助于信号网络可塑性的特征包括：1.对持续刺激的适应或脱敏(反馈调节)。2.在共享关键信号成分的同时维持通路特异性。3.在环境和内在波动存在的情况下开展强劲的活动。4.动态调节通路活动，以编码和传递有关细胞周围环境的信息。5.信号成分的亚细胞位置和活性的动态重组。6.对通路成分中的扰动(例如，信号成分的缺失、过度表达或突变)的缓冲或稳健性。我们认为，正是信号网络的可塑性极大地削弱了单靶点小分子疗法在治疗人类疾病方面的有效性(即经常缺少控制网络激活和功能的单个节点)。我们提出的定义MAPK信号网络可塑性的研究允许对网络中的两个或更多节点进行计算预测和生化、遗传和药理学验证，这些节点的组合扰动将有效地抑制或重建疾病失调网络的正常动力学。该联盟的目标是：1.完成MAPK信号网络的全面定量蛋白质组分析。2.使用高度创新的时空成像技术，对特定的GTP酶和其他控制MAPK信号网络活性的蛋白的活性进行时空成像，并与能够测量同一活细胞中ERK1/2、p38、JNK和ERK5活性的传感器进行多路复用。3.利用生物信息学方法对蛋白质组数据进行标注，并对MAPK信号网络进行分析，为MARK网络的活性和可塑性建模。建模将用于定义MAPK网络的可塑性，并确定对可塑性至关重要的节点。这些模型将在不同刺激、刺激组合以及MAPK信号网络的遗传和小分子扰动的迭代过程中进行实验测试。4.开发用于干扰网络可塑性的节点蛋白小分子抑制剂。这项分析将在细胞模型中进行测试，在细胞模型中，MAPK信号网络的重新布线和失调涉及疾病状态，如转化或耐药。 与公共健康相关：以这种严格的方式定义信号网络可塑性是我们对细胞行为理解的范式转变所必需的，细胞行为的调控失调是影响西半球人的大多数人类疾病的根源。对信号网络可塑性的严格定义将加速将人类疾病的基本发现转化为治疗干预，这是NIH任务的既定目标。

DESCRIPTION (provided by applicant): Signal network plasticity allows cellular responses to vary in behavior according to varying environmental conditions. Features that contribute to signal network plasticity include: 1. Adaptation or desensitization to persistent stimuli (feedback regulation). 2. Maintenance of pathway specificity while sharing key signaling components. 3. Robust activity in the presence of both environmental and intrinsic fluctuations. 4. Dynamical modulation of pathway activity to encode and transmit information about the cell's surroundings. 5. Dynamical reorganization of sub cellular location and activity of signaling components. 6. Buffering against or robustness to perturbations in pathway components (e. g., deletion, over expression or mutation of signaling components). We believe it is the plasticity of signaling networks that has greatly impaired the ability of single target small molecule therapeutics to be effective in treating human disease (i.e., the frequent absence of single nodes controlling network activation and function). Our proposed studies to define plasticity of the MAPK signaling network allows computational predictions and biochemical, genetic and pharmacological validation of two or more nodes within the network whose combinatorial perturbation will effectively inhibit or re-establish normal dynamics of a disease dysregulated network. The goals of the consortium are to: 1. Complete a comprehensive quantitative proteomic analysis of the MAPK signaling network. 2. Use highly innovative spatio-temporal imaging of the activity of specific GTPases and other proteins controlling MAPK signaling network activity multiplexed with sensors that are able to measure the activity of ERK1/2, p38, JNK, and ERK5 in the same living cell. 3. Use bioinformatics methods to annotate the proteomic datasets and MAPK signaling network analysis for modeling of the MARK network activity and plasticity. Modeling will be used to define MAPK network plasticity and to identify nodes that are critical for plasticity. The models will be experimentally tested in an iterative process with different stimuli, combinations of stimuli and genetic and small molecule perturbation of the MAPK signaling network. 4. Develop small molecule inhibitors of node proteins for use in perturbing network plasticity. The analysis will be tested in cell models where rewiring and dysregulation of the MAPK signaling network is involved in a disease state such as transformation or drug resistance. Relevance to public health: Defining signal network plasticity in this rigorous manner is required for paradigm shifts in our understanding of cell behavior whose dysregulation is at the root of most human diseases that affect people in the western hemisphere. A rigorous definition of signal network plasticity will accelerate the translation of basic discovery to therapeutic intervention of human disease, a stated goal of the NIH mission.