CAREER: qBio+cBio=sBio; Identifying the role of cross-family signaling in angiogenesis

生物医学工程中的一个关键挑战是需要控制血管形成过程，也称为“血管生成”。控制血管生成很重要，因为血管为我们的器官和组织提供正常运作所必需的营养。控制癌症血管生成的努力集中在通过切断肿瘤血液供应来饥饿和可能杀死肿瘤上，通常是通过观察一个单一的蛋白质。该项目提出克服目前这种癌症治疗的局限性，并通过解决一个更困难的“大数据”问题来应对控制血管生成的一般挑战：了解蛋白质组合如何控制血管生成。该项目将通过：1)通过实验确定重要的蛋白质特性；2)确定描述这些蛋白质行为的数学方程；3)开发计算机模拟，包括实验数据和数学方程，以确定蛋白质是如何引起血管生成的。该项目的教育和推广部分将在入门级课程中向二年级学生介绍研究和计算机建模，以激发他们对STEM的兴趣。这些活动将包括对代表性不足的学生进行指导，以提高他们对STEM专业的兴趣和坚持。由于血管生成涉及70多种疾病的病理，因此对血管生成的定向控制仍然是迫切需要的。一种有前途的血管生成控制方法涉及超越传统的血管内皮生长因子(VEGF)-VEGF受体（VEGFR）轴的重点，转向新的重点：跨轴信号（跨家族的蛋白质结合）。该项目的目标是通过基于定量生物学（qBio）、计算生物学（cBio）和综合系统生物学（sBio）的三个目标，开拓理解跨轴血管生成信号的转变。定量生物学将用于测量交叉轴结合和相关蛋白质配体的浓度，包括通过开发用于多重测量受体浓度的新定量工具。计算生物学将用于构建有效的交叉轴模型，预测适配器激活如何促进血管生成标志、细胞增殖和迁移。系统生物学将通过qBio和cBio工具在体外血管生成中应用来预测交叉轴信号在血管生成中的作用。将测量配体、受体和接头的浓度，并预测交叉轴信号的大小。这些预测将通过在体外证明血管形成的控制（抑制和刺激）来验证。本研究将与教学相结合，通过核心课程创建本科生研究路径。本课程将向大二学生介绍系统生物学，他们将开发血管生成中配体受体信号的计算模型。学生还将有机会在PI的研究实验室继续他们的工作。将为代表性不足的学生提供额外的指导，以支持他们在STEM领域的坚持。

PI: Imoukhuede, PrincessProposal #: 1653925A critical challenge in biomedical engineering is a need to control the process of blood vessel formation, also known as "angiogenesis." Controlling angiogenesis is important, because blood vessels supply the nutrients necessary for our organs and tissues to function properly. Efforts to control angiogenesis in cancer focus on starving and possibly killing the tumor by cutting off tumor blood supply, typically by looking at a single protein. This project proposes to overcome current limitations in this type of cancer therapy and meet the general challenge of controlling angiogenesis by tackling a more difficult, "big-data"-like problem: understanding how combinations of proteins control angiogenesis. This project will tackle the problem by: 1) experimentally determining important protein characteristics; 2) determining mathematical equations that describe the behaviors of these proteins; and 3) developing computer simulations that include both the experimental data and the mathematical equations to determine how the proteins work to cause angiogenesis. The education and outreach portion of this project will introduce sophomores to research and computer modeling in an introductory-level course in order to excite them about STEM. The activities will include mentoring of underrepresented students to increase their interest and persistence within STEM majors.The directed control of angiogenesis remains a pressing need due to its involvement in the pathology of over 70 diseases. A promising approach for angiogenesis control involves going beyond the traditional emphasis on the vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) axis towards a new focus: cross-axis signaling (protein binding across families). The objective in this project is to pioneer a shift towards understanding cross-axis angiogenic signaling via three aims grounded in quantitative biology (qBio), omputational biology (cBio), and integrative systems biology (sBio). Quantitative biology will be used to measure cross-axis binding and concentrations or relevant protein ligands, including through the development of new quantitative tools for multiplex measurement of receptor concentrations. Computational biology will be used to construct validated cross-axis models that will predict how adapter activation contributes to angiogenic hallmarks, cell proliferation, and migration. Systems biology will be used to predict the role of cross-axis signaling in angiogenesis by applying the qBio and cBio tools to angiogenesis in vitro. Ligand, receptor, and adapterconcentrations will be measured, and the magnitude of cross-axis signaling will be predicted. These predictions will be validated bydemonstrating control of vessel formation (inhibition and stimulation) in vitro. This research will be integrated with teaching by creating undergraduate research pathways via a core course. This will introduce systems biology to sophomore students who will develop computational models of ligand-receptor signaling in angiogenesis. Students will also be offered opportunities to continue their work within the PI's research laboratory. Additional mentoring will be provided to underrepresented students to support their persistence within STEM fields.