Development of a Multiscale Mechanistic Simulation of Acetaminophen Induced Liver

描述（由申请人提供）：药理学和毒理学过程发生在广泛的空间和时间尺度上，包括多个器官系统。计算机毒理学模型中的系统生物学必须包括覆盖与人类医学和毒理学相关的多个尺度和多个组织的子模型。我们将开发一个以肝脏为中心的机制为基础的多尺度硅片模拟框架，用于异种生物毒性和代谢，其中包括四个关键的生物尺度：群体遗传和暴露变异量表生理药代动力学（PBPK）全身量表组织水平和多细胞量表亚细胞信号和代谢途径量表多尺度的计算机模拟将集中在肝脏，在许多毒理学，药理，正常和疾病过程中的关键器官。为了初步模拟对肝脏的毒性挑战，我们将建立一个基于对乙酰氨基酚（APAP）毒性的硅模拟机制。APAP是一种广泛使用的非处方止痛药和退烧药。急性过量服用APAP是西方国家导致肝功能衰竭的主要原因。APAP过量导致小叶中心肝坏死，可发展为肝功能衰竭，在某些情况下患者死亡。我们的多尺度计算机模拟将把现有的各种时空尺度的开源建模工具连接到一个聚合的计算机模型中。这种方法允许我们在个体生物尺度上利用现有的工具、建模方式和模型。此外，这种方法便于在单个尺度上交换模型，而不需要对其他尺度上的子模型进行广泛的修改，并且允许我们利用现有的模型开发工具和资源。完整的多尺度计算机模型将提供一个基于机制的框架，该框架结合了各种尺度的影响，并将提供一个框架来预测临床使用的肝功能和衰竭血清标志物的变化。我们的计算机模拟将使用活体小鼠肝脏的显微成像进行校准，小鼠肝脏

DESCRIPTION (provided by applicant): Pharmacological and toxicological processes occur across a wide range of spatial and temporal scales and include multiple organ systems. A Systems Biology in silico toxicological model must include submodels that cover the multiple scales and the multiple tissues relevant to human medicine and toxicology. We will develop a liver centered mechanism based multiscale in silico simulation framework for xenobiotic toxicity and metabolism that incorporates four key biological scales: Population genetic and exposure variation scale Physiologically Based Pharmacokinetic (PBPK) whole body scale Tissue level and multicellular scale Subcellular signaling and metabolic pathways scales The multiscale in silico simulation will be centered on the liver, a critical organ in many toxicological, pharmacological, normal and disease processes. For our initial simulations of toxic challenge to the liver we will build a mechanism based in silico simulation of Acetaminophen (APAP) toxicity. APAP is a widely used over-the-counter pain reliever and fever reducer. An acute overdose of APAP is a leading cause of liver failure in the western world. APAP overdose leads to centrilobular liver necrosis that can progress to liver failure and in some cases patient death. Our multiscale in silico simulation will link existing open source modeling tools for the various spatiotemporal scales into an aggregate in silico model. This approach allows us to leverage existing tools, modeling modalities and models at the individual biological scales. Furthermore, this approach facilitates swapping models at individual scales without extensive modification of the sub-models at the other scales and allows us to leverage existing model development tools and resources. The complete multiscale in silico model will provide a mechanism based framework that incorporates effects at the various scales and will also provide a framework to predict changes in clinically used serum markers of liver function and failure. Our in silico simulation will be calibrated using microscopic imaging in the liver of a living mouse, mouse liver immune-histology, along with standard histology and serology in animal studies of APAP toxicity. The proposed in silico model is a first step in toxicity prediction 1. 2. 3. 4. simulatio that ultimately will lead to improved techniques for prediction toxicity of therapeutic agents and environmental toxins while simultaneously reducing the need for animal toxicity studies.