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， 对人类生理学、疾病进展和医学治疗的后果。临床结局和 其他的动态效应来自于跨多个尺度的集体行为，不能简单地解释 通过在单一尺度下研究孤立的部分。多尺度系统工程方法允许定量 描述相互关联的过程，这有助于理解之间的联系机制 这些过程在实验中不容易解耦。PI研究计划的总体愿景 名为系统生物医学和制药实验室是开发多尺度计算模型， 建立和求解这些模型的方法，以增强对组织管理机制的理解 重塑和损伤的疾病和感染的结果，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集中在以下过程， 涉及细胞外基质（ECM）的变化，ECM为细胞外基质（ECM）提供生物化学和结构支持， 周围的细胞。为化学和生物过程建立多尺度计算模型， ECM的结构性添加或缺失会损害各种组织， 了解人体组织，并为疾病治疗和预防的进步奠定基础。的 基本原理是，多尺度计算模型提供了对复杂网络的影响， 化学物质如葡萄糖、激素和药物对细胞，组织， 和全身生理水平。拟议的研究解决了编制多个 有助于慢性组织损伤的发生和进展的过程， 计算框架能够将相互关联的化学，物理和生物因素纳入 以耦合方式并以适当的幅度和顺序进行说明，以做出可测试的预测。在 缺乏这样的框架，组织慢性损伤事件的网络将继续瓦解， 这是令人困惑的，有效的药物治疗的发展可能仍然是零碎的， 慢了今后五年的目标是：1）制定加快和促进建设的方法 和重用的多尺度模型和2）创建新的多尺度模型，以改善生理 了解局部和全身免疫刺激剂如何影响关节炎性自身免疫性炎症的损伤 和癌症免疫疗法。这些目标建立在PI实验室为定量系统所采用的方法之上 生物医学和药理学以及它们最近产生的与计算模型有关的结果 适用于糖尿病肾病、结核病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.