CAREER: Mathematical modeling of angiogenesis signaling and crosstalk in tumor cells

该项目将通过靶向血管生成信号通路来确定抑制癌细胞生长所需的新策略。血管生成是由原有血管形成的新血管，对肿瘤的生长和发展至关重要。血管生成因子之间有许多相互作用，肿瘤细胞必须对这些相互作用作出解释和反应。PI建议应用数学模型来解决有关肿瘤细胞中血管生成信号动力学以及串扰和细胞异质性的影响的基本问题。最终，对血管生成途径中涉及的信号事件的详细了解可以导致在包括癌症在内的一系列正常和病变条件下改变血管生成的有效策略。研究目标与多年的推广和教育培训计划紧密结合，以影响从K-12到研究生院的学生。PI将开发一种名为“DrEAMM”（驱动对数学建模的热情）的动手互动课程资源，将数学概念带入生活，并吸引学生进行计算思维。本课题的研究目的是提供肿瘤细胞血管生成信号通路的预测计算模型。为了了解和抑制肿瘤生长，需要对这些信号网络进行定量和分子上的详细描述。为了实现这一目标，PI将构建第一个数学模型，专门确定肿瘤细胞中参与细胞增殖和凋亡的血管生成信号分子的浓度谱。该模型将首次定量描述促血管生成因子和抗血管生成因子的平衡，以及它们在癌细胞中相互作用的含义。PI将使用灵敏度分析来探索参数空间，并使用稳健的数据驱动参数估计技术来将模型拟合到实验测量中，包括PI生成的新数据。该模型将预测平均血管生成信号动力学的细胞群体，以及个别细胞的反应。因此，该项目将包括确定性和随机模拟。该模型将应用于确定能够精确改变血管生成平衡的机制，从而有利于促进细胞死亡的抗血管生成信号物种。完成提出的研究目标的预期结果是通过靶向血管生成信号导致肿瘤凋亡的新策略的分子详细描述。更广泛地说，这项工作可以通过靶向一系列细胞类型和条件下的血管生成信号通路来抑制细胞生长所需的突破性策略。PI将推行一项与拟议研究密切结合的多年外展和教育培训计划。拟议的活动将为从K-12到研究生院的学生带来生活数学概念，并使学生参与计算思维。该教育计划的目标是激发和培养来自弱势群体的K-12学生对STEM领域的热情，并使本科和研究生阶段系统生物学课程中的概念更加生动。

1552065Finley, Stacey This project will identify novel strategies needed for inhibiting cancer cell growth by targeting angiogenesis signaling pathways. Angiogenesis is the formation of new blood vessels from pre-existing vessels and is critical to tumor growth and development. There are many interactions between the angiogenic factors, which tumor cells must interpret and respond to. The PI proposes to apply mathematical modeling to address fundamental questions regarding the dynamics of angiogenesis signaling in tumor cells and the effects of crosstalk and cell heterogeneity. Ultimately, a detailed understanding of the signaling events involved in angiogenesis pathways can lead to effective strategies for altering angiogenesis in a range of normal and diseased conditions, including cancer. The research objectives are tightly integrated with a multi-year outreach and educational training plan to impact students ranging from K-12 through graduate school. The PI will develop a hands-on, interactive curricular resource called 'DrEAMM' (Driving Enthusiasm About Mathematical Modeling) that brings to life mathematical concepts and engages students in computational thinking. The research objective of this proposal is to provide a predictive computational model of angiogenic signaling pathways in tumor cells. A quantitative and molecular-detailed description of these signaling networks is required to understand and inhibit tumor growth. To accomplish this goal, the PI will construct the first mathematical model to specifically identify the concentration profiles of the angiogenesis signaling molecules involved in cell proliferation and apoptosis in tumor cells. The model will establish, for the first time, a quantitative description of the balance of pro- and anti-angiogenic factors and the implications of their crosstalk in cancer cells. The PI will use sensitivity analyses to explore the parameter space and a robust, data-driven parameter estimation technique to fit the model to experimental measurements, including new data generated by the PI. The model will predict the average angiogenesis signaling dynamics of a population of cells, as well as the responses of individual cells. As such, the project will include both deterministic and stochastic simulations. The model will be applied to identify the mechanisms that enable precise shifting of the angiogenic balance in favor of anti-angiogenic signaling species that promote cell death. The expected outcome of completing the proposed research objectives is a molecular-detailed description of novel strategies that lead to tumor apoptosis by targeting angiogenesis signaling. More broadly, this work can lead to breakthrough strategies needed for inhibiting cell growth by targeting angiogenesis signaling pathways in a range of cell types and conditions. The PI will pursue a multi-year outreach and educational training plan closely integrated with the proposed research. The proposed activities will bring to life mathematical concepts for students ranging from K-12 through graduate school and engage the students in computational thinking. The goals for the educational plan are to spark and cultivate enthusiasm in STEM fields among K-12 students from under-represented groups and enliven concepts presented in undergraduate and graduate level systems biology classes.