Center for the Spatiotemporal Modeling of Cell Signaling (STMC)

在NIGMS P20的支持下，新墨西哥州细胞信号时空建模中心(时空建模中心，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、动态、相互作用和生化修饰如何共同决定复杂、相互作用的细胞信号网络的结果；2)装备新一代跨学科研究人员，使其能够成功地从事专注于复杂生物医学过程的定量、系统水平分析的研究；3)建立有效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，将其作为新墨西哥州的长期科学重点领域；以及4)，在系统生物学的新学科中领导提高妇女和少数群体的地位。 这项申请建议STMC被认可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)传递信号，FceRI是过敏和哮喘的关键参与者，并通过与细菌感应性甲酰肽受体(FPR)的正串扰和与IgG受体FceRIIB的负串扰来调节FceRI信号。健壮和易处理的RBL-2H3大鼠嗜碱性白血病细胞仍将是系统定量测量的主要工具。实验团队将量化在信号传递过程中发生的受体、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。膜-近端事件将在时间和空间上与钙离子动员和钙离子依赖性分泌联系在一起。计算团队将开发膜上信号启动和IP3介导的钙动员导致分泌的预测模型。在目标1中，将应用复杂的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制动力学模型。在目标2中，将使用基于代理的3D模拟器来评估受体信号的空间方面，包括聚集、扩散和其他动态的膜近端过程。AIM 3将使用一种新的随机空间模型，以解决细胞几何形状对钙调节的影响，重点是质膜-ER接触部位内ER传感器(STIM)和存储操作通道(Orai家族成员)的耦合，以支持电容进入。系统的剂量反应研究以及药理学和遗传操作将检验模型预测，并验证临床有用干预的新靶点。获得原始人类血液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信令、串扰和结果方面有着长期的记录。他们还拥有在技术上不断创新的记录，这一传统在这里通过发展超分辨率荧光显微镜、创造新型荧光单链抗体(ScFv)以及设计用于细胞激活和分析的微流控平台而得到延续。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研究的能力，并将为中心带来新成员、合作者和少数族裔学生。数据和模型将通过基于网络的工具、活跃的访问者和研讨会计划以及一年一度的高调会议广泛传播。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，特别是其他免疫疾病和癌症有关的其他信号系统。

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.