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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：
9334147
负责人：
DAVID ANDREW LARGAESPADA
金额：
$ 175.68万
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/9334147
关键词：
Affect Alpha Cell 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 Immune response 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 Reproduction spores Science Side Signal Pathway Stratification 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 Twin Multiple Birth Wood material actionable mutation 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 macrophage microsystems migration molecular mechanics multidisciplinary neoplastic cell new therapeutic target novel therapeutic intervention oncology patient stratification patient subsets reverse genetics success treatment strategy tumor tumor microenvironment tumor progression unpublished works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，癌症是由基因改变引发的，这些基因改变驱动了过度活跃的细胞分裂。和细胞迁移。一种常见的治疗策略是靶向经常突变的蛋白质，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就。尽管有大量的公共和私人投资，但仍取得了成功，这可能是由于信号方面的功能冗余这些途径为耐药性的出现提供了多种途径。另一种策略，定义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件。因为正是这些元素上游遗传改变的下游汇合点，这些关键要素的破坏提供了可行的临床相关靶点由于细胞迁移是高级别癌症的共同特征，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以通过复杂的、机械挑战肿瘤微环境。通过直接关注细胞的“螺母和螺栓”，在迁移方面，我们将针对系统中最重要和非冗余的部分。具体来说，我们建议综合建模和实验，以研究细胞迁移的分子力学以及细胞迁移的分子机制。肿瘤微环境作为潜在的癌遗传学的功能调节疾病进展。我们将通过实验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用于：1）通过计算机识别新的药物靶点/靶点组合，2）定义肿瘤的分子力学亚型，用于患者分层，3）指导体外工程，微系统和体内动物模型，以更好地模拟人类疾病，以及4）模拟肿瘤在不同的潜在治疗策略下进展。最后，我们将开发一个模拟器驱动的反向遗传学方法来阐明驱动突变的功能性机械后果，并寻求操纵肿瘤的物理特性以同时偏向免疫抑制细胞，促进抗肿瘤免疫应答。