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; 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.

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信号网络； 2）为新一代的跨学科研究人员提供成功的研究职业，重点是对复杂生物医学过程的定量，系统水平分析； 3）建立有效且可持续的基础设施，以培养和维持系统生物学研究和培训，作为新墨西哥州科学重点的长期领域；和4），领导妇女和少数民族在系统生物学的新学科中的进步。 该申请建议将STMC识别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，以及通过阳性串扰与细菌敏感的emyl肽受体（FPR）和与IGG受体受IGG受体Fceriib的阳性串扰对FCERI信号传导的调节。健壮且可拖动的RBL-2H3大鼠嗜碱性白血病细胞将仍然是系统定量测量的主要工具。实验团队将量化受体以及信号蛋白和信号传导过程中脂质的分布，迁移率，相互作用和磷酸化/去磷酸化。膜 - 螺旋事件将在时间和空间中连接到CA [2+]动员和CA [2+] - 依赖性分泌。计算团队将在膜和IP3介导的Ca2+动员中开发信号启动的预测模型，从而导致分泌。在AIM 1中，将采用基于规则的建模方法来开发由三个受体触发的早期信号事件的机械动力学模型。在AIM 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，扩散和其他动态膜透明过程。 AIM 3将使用新的随机空间模型来解决细胞几何形状对钙调节的影响，重点是在Plasmammbrane-ER接触位点内ER传感器（stim）和储藏式操作的通道（ORAI家族成员）的耦合，以支持电容性。系统的剂量反应研究以及药理学和遗传操作将测试模型预测，并验证临床可用干预措施的新目标。获得原代人血液嗜碱性嗜碱性嗜碱性嗜血杆菌将有直接的临床翻译。 STMC研究团队具有衡量和建模FCERI信号，串扰和结果的长期记录。他们还拥有技术连续创新的记录，这是通过超分辨率荧光显微镜的发展，新型荧光单链ABS（SCFV）以及用于细胞激活和分析的微流体平台的工程技术来扩展的传统。该中心的管理，发展和培训计划将最大化中心成员进行创新科学的能力，并将新的成员，合作者和少数民族学生带到中心。数据和模型将通过基于Web的工具，活跃的访问者和研讨会计划以及年度高调会议大致传播。该中心将强烈支持将新的技术和计算工具转换为与人类疾病有关的其他信号系统，尤其是其他免疫疾病和癌症。