(PQB6)An Integrative Computational and Bioengineered Tissue Model of Metastasis

(PQB6)转移的综合计算和生物工程组织模型

基本信息

批准号：
8730584
负责人：
DAVID B AGUS
金额：
$ 55.77万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-05 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730584
关键词：
Affect Apoptosis Area Biochemical Biological Models Biology Biomechanics Biomedical Engineering Biophysics Blood Vessels Calibration California Cancer Model Cancer Patient Cell Culture Techniques Cells Cessation of life Clinical Colon Carcinoma Colonic Neoplasms Complex Computer Simulation Data Development Dimensions Disease Progression Disseminated Malignant Neoplasm Distant Dose Endothelial Cells Extracellular Matrix Frequencies Future Goals Growth Growth Factor Hepatic Hepatocyte Histology Histopathology Human Hypoxia Image Impairment In Situ In Vitro Individual Laboratories Life Liver Liver parenchyma Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Measurement Mechanics Metabolic Metastatic Neoplasm to the Liver Metastatic to Methods Modeling Molecular Morphology Necrosis Neoplasm Metastasis Organ Organoids Outcome Patients Pharmaceutical Preparations Prognostic Marker Psyche structure Regenerative Medicine Research Resolution Shapes Simulate Site Stem cells Structure System Techniques Testing Therapeutic Time Tissue Engineering Tissue Model Tissues Tumor Cell Invasion Universities Validation Variant biophysical properties cancer cell cancer therapy cell growth forest human data in vivo interdisciplinary approach mathematical model metastatic colorectal neoplastic cell neovascularization novel physical science public health relevance research study scaffold simulation spatiotemporal stem therapeutic target tissue support frame tumor tumor growth tumor microenvironment tumor progression virtual

项目摘要

DESCRIPTION (provided by applicant): Metastatic cancer growth is one of the most challenging areas in cancer treatment. However, metastasis is difficult to study systematically in the laboratory largely due to discrepancies between cell culture models and tumor growth in vivo. Much research has been devoted to defining molecular and biochemical changes during tumor progression, but a deeper understanding of the interaction between cancer cells and the organ microenvironment is crucial to future advances in cancer therapy. Our overall goal is to develop an integrated bioengineered/computational model of metastatic tumor growth to probe the relationships between growth dynamics, heterogeneous microenvironments, and the underlying biophysics. This proposal applies an interdisciplinary approach to cancer metastasis by directly merging the methods of the physical sciences, regenerative medicine, and tissue engineering. A University of Southern California-led multi-institutional team has developed mechanistic, multiscale computational models of vascularized tumor growth in complex virtual tissues. Wake Forest University has developed tissue bioengineering techniques to create functional liver organoids that can be injected with cancer cells and will be used to recapitulate the in vivo milieu of cancer metastasis. We propose to use bioengineering to create living liver tissues in situ with the native structure and function of human livers. The proposed integrated bioengineered/computational platform should give unprecedented spatiotemporal resolution and microenvironmental control of metastatic colon cancer growth. In Aim 1 of this proposal the computational model will be calibrated to data from bioengineered hepatic disc and in situ organoid experiments. Simulation predictions of colon cancer metastatic development will be compared to experiments to quantify accuracy and determine need for model refinements. In Aim 2, the calibrated model will be used to systematically investigate colon tumor growth dynamics under diverse microenvironmental conditions, in which we modulate biophysical parameters by applying mechanical forces, altering oxygenation, and administering therapeutics. We will validate the model's predictions against in situ organoid experiments under these same conditions. In Aim 3, we will calibrate the simulator to patient-derived metastatic colon tumor explants and determine if simulations of tumor growth correspond with imaging and outcome data from the same patients. This project will create a first-of-its-kind integrated computational/bioengineered liver metastasis model, providing a reproducible, controllable system for probing and manipulating the dynamics of metastasis, testing and refining hypotheses, and making predictions that can be extrapolated to human cancer. These integrative modeling efforts will give a new dimension to understanding tumor spread and yield important information about treating cancer metastases.

描述（由申请人提供）：转移性癌症生长是癌症治疗中最具挑战性的领域之一。但是，转移很难系统地研究实验室主要是由于细胞培养模型与体内肿瘤生长之间的差异。许多研究致力于定义肿瘤进展过程中的分子和生化变化，但是对癌细胞与器官微环境之间的相互作用的更深入了解对于未来的癌症治疗进展至关重要。我们的总体目标是开发转移性肿瘤生长的综合生物工程/计算模型，以探测生长动态，异质微环境和基础生物物理学之间的关系。该建议通过直接合并物理科学，再生医学和组织工程的方法来应用跨学科转移方法。一个由南加州大学领导的多机构团队开发了复杂虚拟组织中血管化肿瘤生长的机械，多尺度计算模型。韦克森林大学（Wake Forest University）开发了组织生物工程技术，以创建功能性肝脏类器官，可以注射癌细胞，并将用于概括癌症转移的体内环境。我们建议使用生物工程来与人肝的天然结构和功能原位形成活肝组织。拟议的综合生物工程/计算平台应为转移性结肠癌生长的前所未有的时空分辨率和微环境控制。在本提案的目标1中，计算模型将被校准到来自生物工程的肝盘和原位器官实验的数据。将结肠癌转移性发育的模拟预测与实验进行比较，以量化准确性并确定模型改进的需求。在AIM 2中，校准模型将用于系统地研究各种微环境条件下结肠肿瘤生长动力学，其中我们通过施加机械力，改变氧合和管理治疗方法来调节生物物理参数。在这些相同条件下，我们将验证模型对原位器官实验的预测。在AIM 3中，我们将将模拟器校准为患者衍生的转移性结肠肿瘤外植体，并确定肿瘤生长的模拟是否与同一患者的成像和结果数据相对应。该项目将创建一个初始的集成计算/生物工程化的肝转移模型，为可再现，可控制的系统提供探测和操纵转移，测试和精炼假设的动态，并做出可以将其外推到人类癌症的预测。这些综合建模工作将为了解肿瘤扩散并产生有关治疗癌症转移的重要信息。