Center for the Spatiotemporal Modeling of Cell Signaling (STMC)

细胞信号传导时空建模中心 (STMC)

• 批准号: 8534168
• 负责人: Bridget S Wilson
• 金额: $ 259.34万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534168
• 关键词: Activation Analysis; Address; Affinity; Area; Asthma; Bacteria; Basophilic leukemia; Basophils; Biochemical; Biology; Calcium; Cell membrane; Cells; Clinical; Complex; Coupling; Development; Diffusion; Discipline; Dose; Engineering; Event; Family member; Fluorescence Microscopy; Generations; Goals; Human; Hypersensitivity; IgE Receptors; IgG Receptors; Immune System Diseases; Intervention; Kinetics; Lead; Link; Lipids; Malignant Neoplasms; Measurement; Measures; Mediating; Membrane; Microfluidics; Minority; Modeling; Modification; Motion; National Institute of General Medical Sciences; New Mexico; Online Systems; Outcome; Phosphorylation; Process; Protein Dephosphorylation; Rattus; Receptor Signaling; Records; Regulation; Research; Research Infrastructure; Research Personnel; Research Training; Resolution; Science; Signal Transduction; Signaling Protein; Site; Students; System; Systems Biology; TNFRSF5 gene; Technology; Testing; Time; Training; Translations; Woman; base; career; computerized tools; data modeling; fMet-Leu-Phe receptor; genetic manipulation; human disease; innovation; member; novel; predictive modeling; programs; receptor; response; sensor; spatiotemporal; symposium; tool

With NIGMS P20 support, the New Mexico Center for the Spatiotemporal Modeling of Cell Signaling (Spatiotemporal Modeling Center, STMC) has set in motion an interdisciplinary, inter-institutional program whose principal goals are: 1), to determine how the spatial proximity, dynamics, interactions and biochemical modifications of membrane receptors and signaling proteins together determine the outcome of complex, interacting cell signaling networks; 2) to equip a new generation of interdisciplinary researchers for successful research careers focused on quantitative, systems level analyses of complex biomedical processes; 3) to establish an effective and sustainable infrastructure to nurture and sustain systems biology research and training as a long-term area of scientific emphasis in New Mexico; and 4), to lead the advancement of women and minorities within the new discipline of systems biology. This application proposes the STMC for recognition as the first P50 National Center for Systems Biology in the Southwestern USA. The anchoring biology will remain focused on signaling through the high affinity IgE receptor (FceRI), a key player in allergies and asthma, and on the modulation of FceRI signaling by positive crosstalk with the bacteria-sensing formyl peptide receptor (FPR) and negative crosstalk with the IgG receptor, FceRIIB. The robust and tractable RBL-2H3 rat basophilic leukemia cell will remain the main tool for systematic quantitative measurements. The experimental team will quantify the distributions, mobility, interactions and phosphorylation/dephosphorylation of receptors and signaling proteins and lipids that occur during signaling. Membrane-proximal events will be linked in time and space to Ca[2+] mobilization and to Ca[2+]-dependent secretion. The computational teams will develop predictive models of signal initiation at the membrane and of IP3-mediated Ca2+ mobilization leading to secretion. In Aim 1, sophisticated rules-based modeling approaches will be applied to develop mechanistic kinetic models of early signaling events triggered by the three receptors. In Aim 2, an agent-based 3D simulator will be used to evaluate spatial aspects of receptor signaling, including clustering, diffusion and other dynamic membrane-proximal processes. Aim 3 will use a new stochastic spatial model, to address the impact of cellular geometry on calcium regulation, with an emphasis on coupling of ER sensors (STIMs) and store-operated channels (Orai family members) within plasma membrane-ER contact sites to support capacitative entry. Systematic dose-response studies and pharmacological and genetic manipulations will test model predictions and validate new targets for clinically-useful interventions. Access to primary human blood basophils will enable direct clinical translation. The STMC research teams have long track records of measuring and modeling FceRI signaling, crosstalk and outcomes. They also have track records of continuous innovations in technology, a tradition extended here through developments in super-resolution fluorescence microscopy, in the creation of novel fluorescent single chain Abs (scFvs) and in the engineering of microfluidic platforms for cell activation and analysis. The Center's plans for Administration, Development and Training will maximize the ability of center members to conduct innovative science and will bring new members, collaborators and minority students to the Center. Data and models will be disseminated broadly through web-based tools, an active visitor and seminar program and an annual high profile conference. The Center will strongly support translation of new technical and computational tools to other signaling systems linked to human disease, especially other immune diseases and cancer.

在NIGMS P20的支持下，新墨西哥州细胞信号时空建模中心（时空模拟中心，STMC）已经启动了一个跨学科、跨机构的计划，其主要目标是：1）确定膜受体和信号蛋白的空间邻近性、动力学、相互作用和生化修饰如何共同决定复杂的、相互作用的细胞信号网络的结果; 2）装备新一代的跨学科研究人员成功的研究事业，重点是定量，复杂的生物医学过程的系统水平分析; 3）建立一个有效的和可持续的基础设施，以培育和维持系统生物学研究和培训作为一个长期的科学重点领域在新墨西哥州; 4）在系统生物学这一新学科中领导妇女和少数民族的进步。 本申请建议STMC作为美国西南部第一个P50国家系统生物学中心。锚定生物学将继续专注于通过高亲和力IgE受体（FceRI）（过敏和哮喘的关键参与者）的信号传导，以及通过与细菌敏感甲酰肽受体（FPR）的正串扰和与IgG受体FceRIIB的负串扰来调节FceRI信号传导。RBL-2 H3大鼠嗜碱性白血病细胞的稳健性和易处理性将仍然是系统定量测量的主要工具。实验团队将量化信号传导过程中发生的受体、信号蛋白和脂质的分布、流动性、相互作用和磷酸化/去磷酸化。近膜事件将在时间和空间上与Ca[2+]动员和Ca[2+]依赖性分泌相关联。计算团队将开发细胞膜信号起始和IP 3介导的Ca 2+动员导致分泌的预测模型。在目标1中，复杂的基于规则的建模方法将被应用于开发由三种受体触发的早期信号事件的机械动力学模型。在目标2中，将使用基于代理的3D模拟器来评估受体信号传导的空间方面，包括聚类、扩散和其他动态近膜过程。目的3将使用一种新的随机空间模型，以解决细胞几何结构对钙调节的影响，重点是质膜-ER接触位点内ER传感器（STIM）和储存操纵通道（奥赖家族成员）的耦合，以支持容量进入。系统的剂量反应研究以及药理学和遗传学操作将测试模型预测并验证临床有用的干预措施的新目标。获得原代人血嗜碱性粒细胞将使直接临床转化成为可能。STMC研究团队在测量和建模FceRI信号、串扰和结果方面有着长期的记录。他们还拥有技术不断创新的记录，这一传统通过超分辨率荧光显微镜的发展得到了扩展，创造了新型荧光单链抗体（scFv），并在细胞活化和分析的微流控平台的工程设计中得到了发展。该中心的管理，发展和培训计划将最大限度地提高中心成员进行创新科学的能力，并将为中心带来新成员，合作者和少数民族学生。数据和模型将通过基于网络的工具、一个活跃的访问者和研讨会方案以及一个年度高知名度会议广泛传播。该中心将大力支持将新的技术和计算工具转化为与人类疾病相关的其他信号系统，特别是其他免疫疾病和癌症。