Quantitative Systems Biomedicine and Pharmacology for Multiscale Tissue Damage

项目摘要 化学、物理和生物过程在多个长度和时间尺度上相互作用，并导致 对人类生理、疾病进展和医学治疗的影响。临床结果和 其他动态效应来自多个尺度上的集体行为，不能简单地解释 通过在单一尺度上研究孤立的部分。多尺度系统工程方法允许量化 对相互连接的过程的描述，这有助于理解 在实验中不容易解耦的过程。国际和平研究所研究计划的总体愿景 名为系统生物医学和制药实验室的是开发多尺度计算模型和 建立和求解这些模型以增强对组织调控机制的理解的方法 疾病和感染导致的重塑和损伤，并模拟这些条件的治疗 以改善人类健康。在拟议的研究中考虑的组织损伤侧重于 涉及细胞外基质(ECM)的变化，ECM提供生化和结构支持，以 周围的细胞。为化学和生物过程建立多尺度计算模型 在结构上增加或耗尽细胞外基质，会损害各种组织，将增加基本的机械性能 了解人体组织，并为疾病治疗和预防的进展奠定基础。这个 基本原理是，多尺度计算模型提供了对复杂网络影响的洞察 葡萄糖、激素和药物等化学物质在分子水平上对细胞、组织、 以及整个身体的生理水平。拟议的研究解决了汇编多个 促进慢性组织损伤的发生和发展的过程成为用户友好的系统 能够将相互关联的化学、物理和生物因素纳入 以一种耦合的方式，并以适当的幅度和序列进行计算，以做出可检验的预测。在……里面 没有这样的框架，将继续瓦解组织慢性损伤的事件网络 令人困惑的是，有效药物治疗的开发可能仍然是零碎的和 慢的。今后五年的目标是：1)探索加快和便利建设的办法 和重复使用多尺度模型，以及2)创建新的多尺度模型以改善生理 了解局部和全身免疫兴奋剂如何影响关节炎自身免疫性炎症的损害 和癌症免疫疗法。这些目标建立在PI实验室采用的量化系统方法的基础上 生物医学和药理学及其与计算模型相关的最新结果 适用于糖尿病肾病、肺结核和转移性癌症的多尺度组织损伤。

PROJECT ABSTRACT Chemical, physical, and biological processes interact across multiple length and time scales and lead to consequences for human physiology, disease progression, and medical therapeutics. Clinical outcomes and other dynamic effects emerge from the collective behavior across multiple scales and cannot be explained simply by studying the isolated parts at a single scale. Multiscale systems engineering approaches allow for quantitative descriptions of interconnected processes, which aids understanding of the mechanisms for the links between the processes that cannot be decoupled easily in experiments. The overall vision for the PI's research program titled the Systems Biomedicine & Pharmaceutics Lab is to develop multiscale computational models and methods for building and solving those models to enhance understanding of the mechanisms governing tissue remodeling and damage as a result of diseases and infections and to simulate the treatment of those conditions to improve human health. Tissue damage considered in the proposed research focuses on processes that involve changes to the extracellular matrix (ECM), which provides biochemical and structural support to surrounding cells. Building multiscale computational models for the chemical and biological processes that result in structural addition or depletion of ECM, which damages various tissues, will increase fundamental mechanistic understanding of human tissues and lay the foundation for advances in disease treatment and prevention. The rationale is that multiscale computational models provide insights into the complex network of the effects of molecular level actions of chemicals such as glucose, hormones, and pharmaceuticals on the cellular, tissue, and whole body levels of physiology. The proposed research addresses the critical need to compile the multiple processes that contribute to the onset and progression of chronic tissue damage into user-friendly systematic computational frameworks capable of taking the interconnected chemical, physical, and biological factors into account in a coupled fashion and in the appropriate magnitudes and sequences to make testable predictions. In the absence of such frameworks, unraveling the network of events in the chronic injury of tissues will continue to be perplexing, and the development of effective pharmaceutical treatments will likely remain piecemeal and slow. The goals for the next five years are 1) to develop methods to accelerate and facilitate the construction and reuse of the multiscale models and 2) to create new multiscale models to improve physiological understanding of how local and systemic immune stimulants affect damage in arthritic autoimmune inflammation and cancer immunotherapy. These goals build upon methods the PI's lab has adopted for quantitative systems biomedicine and pharmacology and the recent results they have produced related to computational models applied to multiscale tissue damage in diabetic kidney disease, tuberculosis, and metastatic cancer.