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(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：
8591092
负责人：
DAVID B AGUS
金额：
$ 59.01万
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/8591092
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 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(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。然而，很难对转移进行系统的研究。这在很大程度上是由于细胞培养模型和体内肿瘤生长之间的差异。许多研究致力于确定肿瘤进展过程中的分子和生化变化，但更深入地了解癌细胞与器官微环境之间的相互作用对于未来癌症治疗的进展至关重要。我们的总体目标是开发一个转移性肿瘤生长的集成生物工程/计算模型，以探索生长动力学、异质微环境和潜在生物物理之间的关系。这项建议通过直接融合物理科学、再生医学和组织工程学的方法，将跨学科的方法应用于癌症转移。南加州大学领导的一个多机构团队开发了复杂虚拟组织中血管肿瘤生长的机械、多尺度计算模型。维克森林大学开发了组织生物工程技术，以创造出可注入癌细胞的功能性肝脏有机化合物，并将用于概述癌症转移的体内环境。我们建议使用生物工程学在原位创造具有人类肝脏天然结构和功能的活肝组织。提出的集成生物工程/计算平台将为转移性结肠癌的生长提供前所未有的时空分辨率和微环境控制。在这项建议的目标1中，计算模型将根据生物工程肝盘和原位有机物实验的数据进行校准。对结肠癌转移发展的模拟预测将与实验进行比较，以量化准确性并确定模型改进的必要性。在目标2中，校准的模型将被用来系统地研究不同微环境条件下的结肠癌生长动力学，其中我们通过施加机械力、改变氧合和给药来调节生物物理参数。我们将在这些相同的条件下，通过原位有机物实验来验证模型的预测。在目标3中，我们将对患者来源的转移性结肠肿瘤外植体校准模拟器，并确定肿瘤生长模拟是否与来自相同患者的成像和结果数据相一致。该项目将创建首个此类集成的计算/生物工程肝脏转移模型，提供一个可重复、可控的系统，用于探测和操纵转移的动力学，测试和完善假说，并做出可以推断为人类癌症的预测。这些综合的建模工作将为理解肿瘤扩散提供一个新的维度，并产生关于治疗癌症转移的重要信息。