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

在肿瘤生长、生物发育和再生医学的背景下，血管生成的控制一直是众多研究的目标，但目前还没有模型具有证明的预测能力。主要研究者（pi）认为导致毛细血管形态发生的复杂生物过程是基于全局广播信号、有限近邻通信和反馈控制随机决策的细胞水平决策的结果。综合这些因素，细胞被编程为遵循几种状态轨迹中的一种，这些状态轨迹可以被描述为静止、分裂或迁移和毛细血管形成。pi已经有证据指向这种类型的行为，并且已经能够识别接受血管生成刺激的细胞亚群，这些细胞要么是迁移的，要么是有丝分裂的。为了更好的理解和具有预测能力的实用工具，pi建议通过应用现代控制理论原理来模拟血管生成。每个单独的单元将被建模为一个独立的单元，响应一组局部和全局控制。该项目在了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，这些研究可能对含有一种或多种细胞类型的体外系统的创建产生直接影响，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。这个项目融合了近年来快速发展的两个领域：随机控制理论和血管生成。这些努力的结合将证明对这两个领域都是无价的。该提案解决了两大挑战：1。提高细胞和生物分子行为的知识，作为耦合物理和生化刺激组合的相互作用功能；和2。开发定量建模和模拟方法，忠实地复制基于实验数据的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.