EFRI-CBE: A Multifaceted Approach to the Modeling of Angiogenesis

PI姓名：R. D。Kamm机构：马萨诸塞州理工学院提案号：0735997 EFRI-CBE：血管生成建模的多方面方法摘要血管生成的控制一直是肿瘤生长、生物发育和再生医学背景下众多研究的目标，但目前还不存在具有证明预测能力的模型。主要研究者（PI）将导致毛细血管形态发生的复杂生物学过程视为细胞水平决策的结果，这些决策基于全球广播信号，有限的近邻通信和具有反馈控制的随机决策。综合这些因素，细胞变得编程遵循几种状态轨迹之一，这些轨迹可以被表征为静止，分裂或迁移和毛细血管形成。PI已经有证据表明这种行为，并且已经能够识别接受血管生成刺激的细胞亚群，这些细胞是迁移的或有丝分裂的。为了满足更好的理解和具有预测能力的实用工具的需求，PI建议通过应用现代控制理论原理来模拟血管生成。每个细胞将被模拟为一个独立的单元，对一组局部和全局控制做出反应。这个项目在理解体外血管生成方面的直接目标以及在癌症、再生医学和发育生物学中血管网络生长的更广泛背景下都很重要。因此，这些研究可能对创建含有一种或多种细胞类型的体外系统产生直接影响，这些细胞类型可用于模拟特定器官的功能，从而促进新药的发现或用于毒性筛选。该项目融合了近年来迅速发展的两个领域：随机控制理论和血管生成。这些努力的结合对这两个领域都是非常宝贵的。该提案涉及两个重大挑战：1。为了提高知识的细胞和生物分子的行为作为耦合的物理和生化刺激的组合的交互功能;和2。开发定量建模和模拟方法，忠实地复制细胞和细胞相互作用的复杂性，并创造性地处理分层细胞系统。

PI name: R.D. Kamm Institution: Massachusetts Institute of Technology Proposal Number: 0735997 EFRI-CBE: A Mulifaceted Approach to the Modeling of Angiogenesis AbstractControl of angiogenesis has been the aim of numerous studies in the context of tumor growth, biological development, and regenerative medicine, yet no models currently exist with demonstrated predictive capabilities. The Principal Investigators (PIs) view the complex biological processes leading to capillary morphogenesis as a consequence of cell-level decisions that are based on global broadcast signals, limited near-neighbor communication, and stochastic decision-making with feedback control. Integrating these factors, a cell becomes programmed to follow one of several state trajectories that could be characterized as quiescence, division, or migration and capillary formation. The PIs already have evidence that points to this type of behavior, and have been able to identify sub-populations of cells receiving angiogenic stimuli that are either migratory or mitotic. To address the needs for greater understanding and for a practical tool with predictive capabilities, the PIs propose to model angiogenesis by applying modern control theory principles. Each individual cell will be modeled as an independent unit responding to set of local and global controls.This project is important both in terms of its immediate goals with respect to understanding in vitro angiogenesis, and in the broader context of vascular network growth in cancer, regenerative medicine and developmental biology. These studies could therefore have immediate impact on the creation of in vitro systems containing one or multiple cell types that could be used to mimic the function of a particular organ, thereby facilitating the discovery of new drugs or for use in toxicity screening. This project merges two fields that have been rapidly developing in recent years with minimal interaction: stochastic control theory and angiogenesis. A combination of these efforts should prove invaluable to both fields. Two grand challenges are addressed in this proposal: 1. To enhance knowledge of cellular and biomolecular behavior as an interactive function of a combination of coupled physical and biochemical stimuli; and 2. To develop quantitative modeling and simulation methods that faithfully replicate the complexity of cell and cellular interactions based on experimental data and deal creatively with the hierarchical cellular systems.