Center for Spatiotemporal Modeling of Cell Signaling

描述（由申请人提供）：本申请寻求nigms支持的新墨西哥细胞信号时空建模中心（时空建模中心；STMC）的竞争性更新。我们的中心在生物学，技术，建模和模拟方面具有显著的优势，以了解膜受体和信号蛋白的空间接近性，动力学，相互作用和运输如何共同决定信号转导网络的结果。研究重点包括ITAM免疫受体家族，特别是高亲和力IgE受体（Fc¿RI），它负责触发过敏性炎症的症状和进展。先天免疫受体Dectin-1具有截断的“hemITAM”，其新的信号控制将在更新期间详细研究。STMC的研究人员还专门研究EGFR和其他受体酪氨酸激酶。该提案的主要焦点是EGFR/erbB受体和Met/Ron家族之间不寻常的串扰，以及它们对癌变和转移的复杂控制。实验团队将量化暴露于配体后介导信号传导和运输的受体和接头的分布、移动性、相互作用和翻译后修饰。每个研究项目都高度整合了实验和数学建模组件。STMC建模和生物信息学核心的计算专家包括基于规则的建模方法领域的先驱，这些方法被应用于开发机械动力学模型和实现强大的空间随机平台，这些平台考虑了膜景观对受体信号的贡献。体内和硅肿瘤模型将为erbB和Met受体控制靶向治疗反应的机制提供见解。多个新技术将在项目中部署，包括实时共聚焦和高光谱显微镜与量子点标记的配体，以跟踪受体分布和活细胞中的相互作用，活细胞的新型TIRF成像分析，光漂白协议

DESCRIPTION (provided by applicant): This application seeks competitive renewal of the NIGMS-supported New Mexico Center for the Spatiotemporal Modeling of Cell Signaling (Spatiotemporal Modeling Center; STMC). Our Center focuses remarkable strengths in biology, technology, modeling and simulation on understanding how the spatial proximity, dynamics, interactions and trafficking of membrane receptors and signaling proteins together determine the outcome of signal transduction networks. Research foci include the ITAM family of immunoreceptors, particularly the high affinity IgE receptor (Fc¿RI) that is responsible for triggering both the symptoms and progression of allergic inflammation. The innate immune receptor, Dectin-1, bears a truncated "hemITAM" and its novel signaling control will be studied in detail over the renewal period. STMC researchers also specialize in the EGFR and other receptor tyrosine kinases. A major focus in this proposal is the unusual cross-talk between EGFR/erbB receptors and the Met/Ron family - and their complex control of carcinogenesis and metastasis. The experimental teams will quantify the distributions, mobility, interactions and post-translational modifications of receptors and adaptors that mediate both signaling and trafficking after exposure to ligand. Each research project is highly integrated with respect to experimental and mathematical modeling components. Computational specialists in the STMC's Modeling and Bioinformatics Core include pioneers in the field of rule-based modeling approaches, which are applied to develop mechanistic kinetic models and to implement powerful spatial stochastic platforms that consider the contribution of the membrane landscape to receptor signaling. In vivo and in silico tumor models will provide insights into the mechanisms by which the erbB and Met receptors control responses to targeted therapies. Multiple new technologies will be deployed within the projects, including real-time confocal and hyper-spectral microscopy with quantum dot- tagged ligands to track receptor distributions and interactions in live cells, novel TIRF imaging assays on live cells, photo-bleaching protocols that quantify protein-protein reaction kinetics, and novel microfluidic devices to image events in rare primary cells and quantify the release of mediators. The STMC community is supported by strong cores. The STMC Super-resolution and Image Analysis Core provides new instrumentation and probes to access protein-protein dynamics at the 10 nm scale and is dedicated to the improved analysis and cross-platform integration of image data, as well as the archiving and sharing of both image and biochemical data, and the broad dissemination of data, code and models. The STMC Training and Outreach Core provides exceptional opportunities for young biomedical, mathematical, statistical, physical and computational scientists, as well as engineers and physicians, to build exciting and productive careers with potential to impact human health. The STMC Administration Core maximizes the ability of center members to conduct innovative science and will continue to support our aspiration to serve as a national model for diversity in Systems Biology through the continued recruitment and advancement of women and minorities.