Center for Spatiotemporal Modeling of Cell Signaling

细胞信号传导时空建模中心

• 批准号: 8919387
• 负责人: Bridget S Wilson
• 金额: $ 221.68万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919387
• 关键词: Adaptor Signaling Protein; Adhesions; Affinity; Allergens; Allergic inflammation; Archives; Area; Asthma; Basophils; Biochemical; Bioinformatics; Biological Assay; Biological Models; Biology; Cancer Control; Cell membrane; Cells; Clathrin; Code; Colon Carcinoma; Communicable Diseases; Communities; Complex; Computer Simulation; Coupled; Data; Data Analyses; Data Set; Dendritic Cells; Development; Diffusion; Discipline; Dissociation; Drug Combinations; Education and Outreach; Endosomes; Engineering; Enzymes; Epidermal Growth Factor Receptor; Evaluation; Event; Experimental Models; Exposure to; Family; Flow Cytometry; Fluorescence; GTP Binding; Generations; Goals; Growth Factor Receptors; Health; Human; Hydrolysis; Hypersensitivity; ITAM; IgE Receptors; Image; Image Analysis; Immune; Immune System Diseases; Immunologic Receptors; Immunology; Inflammation Mediators; Kinetics; Lead; Life; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mediator of activation protein; Membrane; Membrane Protein Traffic; Methods; Microfluidic Microchips; Microscopy; Minority; Modeling; Modification; Mutagenesis; National Institute of General Medical Sciences; Natural Immunity; Neoplasm Metastasis; New Mexico; Online Systems; Outcome; Output; Ovary; Pathway interactions; Pattern; Physicians; Post-Translational Protein Processing; Process; Protein Dynamics; Protein Isoforms; Proteins; Protocols documentation; Quantum Dots; Reaction; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recombinants; Regulation; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Resolution; Role; Science; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Site; Small Interfering RNA; Specialist; Students; Surface; Symptoms; System; Systems Biology; Technology; Time; Training Programs; Translations; Ursidae Family; Woman; Xenograft Model; adaptive immunity; base; carcinogenesis; career; computerized tools; dectin 1; differential expression; fungus; high throughput screening; human disease; imaging modality; improved; in vivo; innovation; insight; instrumentation; intravital imaging; mathematical model; meetings; member; migration; models and simulation; mutant; new technology; novel; particle; pathogen; predictive modeling; programs; protein transport; public health relevance; receptor; receptor internalization; response; single molecule; spatiotemporal; symposium; targeted treatment; tool; trafficking; tumor; web site

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.

描述（由申请人提供）：本申请寻求NIGMS支持的新墨西哥州细胞信号时空建模中心（时空建模中心; STMC）的竞争性更新。我们的中心专注于生物学，技术，建模和模拟的显着优势，了解空间接近，动力学，相互作用和膜受体和信号蛋白的贩运共同决定信号转导网络的结果。研究重点包括免疫受体的ITAM家族，特别是负责触发过敏性炎症的症状和进展的高亲和力IgE受体（Fc <$RI）。先天性免疫受体，Dectin-1，带有一个截短的“hemITAM”，其新的信号转导控制将在更新期间进行详细研究。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/罗恩家族之间的不寻常的串扰-以及它们对癌发生和转移的复杂控制。实验团队将量化受体和衔接子的分布，流动性，相互作用和翻译后修饰，这些受体和衔接子在暴露于配体后介导信号传导和贩运。每个研究项目都高度集成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，这些方法用于开发机械动力学模型，并实现考虑膜景观对受体信号传导的贡献的强大空间随机平台。体内和计算机肿瘤模型将提供对erbB和Met受体控制靶向治疗反应的机制的见解。多项新技术将在项目中部署，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，新的TIRF活细胞成像分析，光漂白协议， 定量蛋白质-蛋白质反应动力学，以及新型微流体装置，用于成像稀有原代细胞中的事件并定量介质的释放。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10 nm尺度的蛋白质-蛋白质动力学，并致力于改进图像数据的分析和跨平台集成，以及图像和生化数据的存档和共享，以及数据，代码和模型的广泛传播。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提供了绝佳的机会，以建立令人兴奋且富有成效的职业生涯，并有可能影响人类健康。STMC行政核心最大限度地提高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，通过继续招聘和提高妇女和少数民族的地位，成为系统生物学多样性的国家典范。