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Center for Modeling Tumor Cell Migration Mechanics

肿瘤细胞迁移机制建模中心

基本信息

批准号：
9753166
负责人：
DAVID ANDREW LARGAESPADA
金额：
$ 212.71万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-17 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753166
关键词：
3-Dimensional Affect Animal Model Animals Attention Automobile Driving Biomechanics Biomedical Engineering Biomedical Technology Cancer Center Cancer Etiology Cancer Immunology Science Cancer Patient Carcinoma Cell Proliferation Cell division Cell model Cells Cessation of life Characteristics Chemistry Cities Clinic Clinical Clinical Trials Complex Computer Simulation Disease Disease Progression Drug resistance Education and Outreach Elements Engineered Gene Engineering Environment Funding Future Genetic Genetic Screening Genome engineering Geographic Locations Goals Human Hyperactive behavior Immune In Vitro Industrialization Inflammation Institutes Investments Lead Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of pancreas Mathematics Mayo Clinic Cancer Center Mechanics Microfluidics Modeling Molecular Molecular Genetics Molecular Motors Motor Mus Mutate Mutation Neoplasm Metastasis Oncogenes Oncologist Pathway interactions Phenotype Physics Premalignant Privatization Process Proteins Publishing Science Side Signal Pathway Structure Suppressor-Effector T-Lymphocytes System T-Lymphocyte Testing The Cancer Genome Atlas Therapeutic Time Tissue Engineering Traction Tumor Biology Tumor Cell Migration Tumor Subtype Tumor-Derived Tumor-associated macrophages Twin Multiple Birth Wood material actionable mutation anti-tumor immune response base biomathematics cancer cell cancer genetics cancer genome cancer type cell behavior cell motility clinically relevant design experimental study extracellular gene discovery gene therapy genetic approach genome sequencing human disease in vivo microsystems migration molecular mechanics multidisciplinary neoplastic cell new therapeutic target novel therapeutic intervention oncology patient stratification reverse genetics success treatment strategy tumor tumor microenvironment tumor progression unpublished works

项目摘要

Abstract At their most fundamental level, cancers are initiated by genetic alterations that drive hyperactive cell division and cell migration. A common therapeutic strategy has been to target the proteins in the often-mutated signaling pathways that regulate cell proliferation. However, so far this strategy has achieved only limited success despite large public and private investment, which is likely due to functional redundancies in signaling pathways that give multiple avenues for the emergence of drug-resistance. An alternative strategy, which defines the organizing framework of our Center, is to directly target the internal or external mechanical machinery or structural elements that drive cell migration. As it is these elements that serve as the most downstream convergence point of the upstream genetic alterations, disruption of these critical elements provides viable, clinically-relevant targets. Since cell migration is a common feature of high-grade cancer, and invasion and metastasis are the primary cause of cancer related death, our Center will focus on understanding the fundamental mechanics and chemistry of how cells generate forces to move through complex and mechanically challenging tumor microenvironments. By focusing directly on the “nuts and bolts” of cell migration, we will be targeting the most vital and non-redundant part of the system. Specifically, we propose integrated modeling and experiments to investigate the molecular mechanics of cell migration and how the tumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. We will experimentally test our computational cell migration simulator, v1.0 (CMS1.0) for the mechanical dynamics of cell migration that will ultimately be used to: 1) identify novel drug targets/target combinations in silico, 2) define molecular mechanical subtypes of tumors for patient stratification, 3) guide the engineering of in vitro microsystems and in vivo animal models to better mimic the human disease, and 4) simulate tumor progression under different potential treatment strategies. Finally, we will develop a simulator-driven reverse genetics approach to elucidate the functional mechanical consequences of driver mutations and seek to manipulate the physical characteristics of a tumor to simultaneously bias against immune suppressor cells and promote the antitumor immune response.

摘要在最基本的层面上，癌症是由驱动过度活跃的细胞分裂的基因改变引发的和细胞迁移。一种常见的治疗策略是针对经常突变的调节细胞增殖的信号通路。然而，到目前为止，这一战略只取得了有限的成果。尽管有大量公共和私人投资，但仍取得了成功，这很可能是由于信令中的职能冗余为出现抗药性提供多种途径的途径。另一种战略，即明确了我们中心的组织框架，是直接针对内部或外部的机械驱动细胞迁移的机械或结构元素。因为正是这些元素充当了最重要的下游汇聚点的上游基因突变，破坏了这些关键要素提供了可行的、与临床相关的靶点。由于细胞迁移是高级别癌症的共同特征，而且侵袭和转移是癌症相关死亡的主要原因，我们中心将重点了解细胞如何产生力量以穿过复杂和复杂的具有机械挑战性的肿瘤微环境。通过直接关注细胞的“螺母和螺栓” 在迁移方面，我们将把目标对准系统中最重要和最非冗余的部分。具体来说，我们建议综合建模和实验来研究细胞迁移的分子机制以及细胞如何肿瘤微环境作为潜在的癌症遗传学的函数来调节疾病的进展。我们将在实验中测试我们的计算细胞迁移模拟器v1.0(CMS1.0)的机械动力学最终将被用于：1)在硅胶中识别新的药物靶点/靶点组合，2) 确定肿瘤的分子力学亚型，用于患者分层，3)指导体外工程微系统和活体动物模型以更好地模拟人类疾病，以及4)模拟肿瘤在不同潜在治疗策略下的进展。最后，我们将开发一种模拟器驱动的反求用遗传学方法阐明驱动突变的功能力学后果，并寻求操纵肿瘤的物理特征以同时偏向免疫抑制细胞和促进抗肿瘤免疫反应。