Super-Resolution and Data Analysis

总结 本申请寻求NIGMS支持的新墨西哥州中心的竞争性续期， 细胞信号的时空建模（时空建模中心; STMC）。我们的中心专注于 在生物学、技术、建模和模拟方面的显著优势， 膜受体和信号蛋白的接近、动力学、相互作用和运输 决定信号转导网络的结果。研究重点包括ITAM家族， 免疫受体，特别是高亲和力IgE受体（FcεRI），负责触发免疫反应， 过敏性炎症的症状和进展。先天免疫受体Dectin-1具有截短的 “hemITAM”及其新颖的信号控制将在更新期间进行详细研究。STMC研究人员 还专门研究EGFR和其他受体酪氨酸激酶。该提案的一个主要重点是 EGFR/erbB受体和Met/罗恩家族之间的相互作用-及其对 致癌和转移。实验小组将量化这些物质的分布、流动性、相互作用 以及介导信号传导和运输的受体和衔接子的翻译后修饰， 暴露于配体。每个研究项目在实验和数学方面都是高度集成的。 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，用于开发机械动力学 模型，并实现强大的空间随机平台，考虑到膜的贡献 景观到受体信号传导。体内和计算机肿瘤模型将通过以下方式提供对机制的见解： erbB和Met受体控制对靶向治疗的反应。多项新技术将在 部署在项目中，包括实时共聚焦和超光谱显微镜与量子点- 标记的配体，以跟踪活细胞中的受体分布和相互作用， 细胞，量化蛋白质-蛋白质反应动力学的光漂白方案，以及新的微流体装置， 在罕见的原代细胞中成像事件并量化介质的释放。 STMC社区由强大的核心支持。STMC超分辨率和图像分析核心 提供了新的仪器和探针，以访问蛋白质-蛋白质动力学在10纳米尺度， 致力于改进图像数据的分析和跨平台集成，以及存档和 共享图像和生化数据，广泛传播数据、代码和模型。的 STMC培训和外展核心为年轻的生物医学，数学， 统计，物理和计算科学家，以及工程师和医生，建立令人兴奋的， 有潜力影响人类健康的生产性职业。STMC管理核心最大化了 中心成员进行创新科学的能力，并将继续支持我们的愿望， 通过持续招募和促进系统生物学多样性的国家模式 妇女和少数民族。

SUMMARY 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 (FcεRI) 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.