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CAREER: Multi-Gradient Microtissue Arrays to Analyze Patient-Derived Cancer Cell Modulation by Combinatorial Electrical and Chemical Stimulation

职业：多梯度微组织阵列通过电和化学组合刺激分析患者来源的癌细胞调节

基本信息

批准号：
1652112
负责人：
Scott Verbridge
金额：
$ 50.42万
依托单位：
Virginia Polytechnic Institute and State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2023-03-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1652112&HistoricalAwards=false
关键词：
CAREER Multi Gradient Microtissue Arrays

项目摘要

PI: Verbridge, Scott S.Proposal #: 1652112Cancer is the second leading cause of death in the United States, with some of the poorest results being for highly infiltrative brain tumor glioblastomas (GBMs), for which the 5-year survival rate is less than 10% even with combination treatments of surgery, radiation and chemotherapy (drugs). Surgery and drugs fail to eliminate the malignant cells that infiltrate centimeters beyond the bulk central mass and radiotherapies damage healthy and malignant tissues alike. This project builds on preliminary studies in tissue-engineered models of GBM that demonstrate that pulsed electric fields (PEFs) induce selective destruction of tumor cells by targeting their altered electrical properties, e.g., changes in surface charge, membrane capacitance and ion channel expression. Furthermore, this effect, which targets a physical hallmark of the tumor leaving normal cells relatively unaffected, is enhanced by the addition of drug therapies, which target alterations in tumor cell chemical properties. The goal of this project is to develop a platform to enable efficient screening of the effects of combined physical/drug treatments on patient-derived cells. This novel platform will expand understanding of the beneficial effects of the combined approach and underpin basic science and clinically important advances in a new precision medicine paradigm. The education and outreach plan includes: 1) expanding the "Cancer Engineering" curriculum, outreach, and diversity at Virginia Tech through new and updated courses, research training opportunities for graduate and undergraduate students and supporting K-12 activities for economically disadvantaged students in Southwest Virginia and 2) establishing an "Ask a Virginia Tech Scientist" web column, which will cover a wide spectrum of topics in science, technology, engineering and math (STEM), for local K-12 students and teachers and community engagement. Effective precision cancer medicine protocols will ultimately depend on multi-targeted therapies to treat highly heterogeneous and adaptable tumors such as GBM. The platform developed in this project will be the very first tissue array microchip with an overlay of multiple types of dynamic therapeutic gradients (e.g. electric field amplitude and drug concentration) in orthogonal directions. The platform will be compatible with high-resolution live measurement of cellular dynamics, and coupled to powerful microfluidic molecular analysis to characterize the epigenomic alterations in stimulated cells, uniquely enabling broad-spectrum parametric analysis of combinatorial electrical/molecular treatments of patient-derived cells. The research plan is organized under three objectives: 1) develop a multi-dimensional electrical/chemical gradient microtissue array chip compatible with high-resolution confocal imaging and impedance measurement, 2) develop high-resolution epigenomic analysis with novel coupling to microfluidic chromatin-immunoprecipitation (ChIP), and 3) execute broad-spectrum parametric studies of combinatorial electrical/chemical treatments using patient GBM cells. Successful completion of these objectives will be crucial to: 1) reveal therapeutic synergies possible through a combination of PEFs and drugs, 2) optimize combinatorial treatments with minimal input material (e.g. cells, reagents), and 3) test molecular hypotheses related to treatment synergies. The data collected will provide basic science insights for a new and effective treatment strategy for infiltrative tumors. The combined physical and chemical approaches to targeting both the dense core, as well as the diffuse infiltrative zones will potentially altering the paradigm of GBM treatment.

PI：Verbridge，Scott S.Proposal#：1652112癌症是美国第二大死因，其中一些最糟糕的结果是高浸润性脑肿瘤胶质母细胞瘤(GBM)，即使采用手术、放射和化疗(药物)的联合治疗，其5年存活率也不到10%。手术和药物无法消除渗透到大块中心肿块外几厘米的恶性细胞，放射治疗对健康和恶性组织的损害都是一样的。该项目建立在GBM组织工程模型的初步研究基础上，该模型表明，脉冲电场(PEF)通过靶向肿瘤细胞改变的电特性，例如表面电荷、膜电容和离子通道表达的变化，来诱导肿瘤细胞的选择性破坏。此外，这种作用针对的是肿瘤的物理特征，而正常细胞相对不受影响，这种作用因药物治疗的增加而得到加强，药物治疗的目标是改变肿瘤细胞的化学性质。该项目的目标是开发一个平台，以便能够有效地筛选物理/药物联合治疗对患者来源细胞的影响。这一新的平台将扩大对联合方法的有益影响的理解，并为基础科学和临床上重要的新精确医学范例的进展奠定基础。教育和外展计划包括：1)通过新的和更新的课程，为研究生和本科生提供研究培训机会，并支持针对弗吉尼亚州西南部经济困难学生的K-12活动，扩大弗吉尼亚理工大学的“癌症工程”课程、拓展范围和多样性；2)为当地的K-12学生和教师以及社区参与建立一个“询问弗吉尼亚理工大学科学家”网络专栏，该专栏将涵盖科学、技术、工程和数学(STEM)的广泛主题。有效的精确癌症医学方案最终将依赖于多靶点治疗来治疗高度异质性和适应性强的肿瘤，如GBM。该项目开发的平台将是第一个在垂直方向上覆盖多种动态治疗梯度(如电场幅度和药物浓度)的组织阵列微芯片。该平台将兼容细胞动力学的高分辨率实时测量，并与强大的微流控分子分析相结合，以表征刺激细胞中的表观基因组变化，从而独特地实现患者来源细胞的组合电气/分子治疗的广谱参数分析。该研究计划安排在三个目标下：1)开发与高分辨率共聚焦成像和阻抗测量兼容的多维电/化学梯度微组织阵列芯片，2)开发与微流控染色质免疫沉淀(CHIP)新型耦合的高分辨率表观基因组分析，以及3)使用患者GBM细胞进行组合电/化学治疗的广谱参数研究。这些目标的成功完成将对以下方面至关重要：1)通过PEF和药物的组合揭示可能的治疗协同效应；2)以最少的输入材料(例如细胞、试剂)优化组合治疗；以及3)测试与治疗协同作用相关的分子假说。收集的数据将为浸润性肿瘤的新的有效治疗策略提供基本的科学见解。以致密核心和弥漫浸润区为靶点的综合物理和化学方法可能会改变GBM的治疗模式。