CAREER: Mechanisms of Drug Resistance in a Responsive Biomaterial Platform

职业：响应性生物材料平台中的耐药机制

基本信息

批准号：
1454806
负责人：
Shelly Peyton
金额：
$ 50.02万
依托单位：
University of Massachusetts Amherst
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1454806&HistoricalAwards=false
关键词：
CAREER Mechanisms Drug Resistance Responsive

项目摘要

Non-Technical:This CAREER award by the Biomaterials program in the Division of Materials Research to University of Massachusetts at Amherst is to develop novel materials that can capture human tissue properties in a controlled, reproducible, and economical fashion. It is cofunded by the BioMaps program and funds from the ENG/CBET/BBBE program. At present, new drugs are developed by screening hundreds of possible candidates against cancer cells grown on plastic surfaces. Drugs that show potential are further tested in animals, and anywhere from zero to a handful of candidates could make it through this process, where they are then taken to clinical trials. Drug candidates that appear successful in cells on the plastic surfaces often fail in clinical trials. Overall, this process is long and not cost effective. The biomaterials that are being studied have potential use in understanding how cancer cells respond to drugs in an environment that mimics human tissue, and thereby overcomes some of the drawbacks of the present approaches. With this award, the PI plans to develop new educational opportunities for students from high school to graduate levels. High school students, especially women will be trained in the PI's laboratory during the summer months, where these students can learn how to do cell culture and 3D printing techniques and to observe how cells move and grow on different material surfaces. Undergraduate students will be trained in creating new pathways to take ownership and authorship of their learning experience, resulting in educational modules that can be used across the nation. At the graduate level, the focus will be in recruiting highly capable students from underrepresented groups across the nation to become the next leading scientists working at the interface of materials and biology. Technical:The ability of cells to resist chemotherapy impacts cancer patients around the globe. A core problem of the current drug screening techniques that utilize plastic multi-well plates is that it fails to account for a cell's native material microenvironment. This CAREER project will take a transformative approach to drug screening by quantifying cancer cell responses to drugs in a biomaterial platform mimicking the rapidly evolving material properties of the tumor microenvironment, specifically a material microenvironment that is continually remodeled by resident mesenchymal stem cells (MSCs). This proposal will use a high-throughput biomaterial platform to determine how three dimensional matrix stiffness, integrin binding, and soluble growth factors and cytokines impact cancer cell response to drugs. The underlying hypothesis is that physical and biochemical cues from an MSC-remodeled extracellular matrix (ECM) interfere with the efficacy small molecule drugs, and that targeting the MSCs, not the cancer cells, can halt this drug resistance. The results from this proposal would transform our fundamental understanding of the role that the physical environment plays in interfering with small molecule drugs. The PI will leverage CAREER funding to increase educational opportunities in bioengineering at three levels: high school, undergraduate, and graduate. The PI has already created a new summer laboratory program at University of Massachusetts at Amherst that teaches high school students cell culture and advanced microscopy techniques. Over the next few years, the PI plans to create new educational modules for undergraduate students that are specifically aimed at self-directed learning techniques and fostering creativity and teamwork in the classroom. Additionally, the PI plans to expand recruiting efforts nationwide, in collaboration with the Diversity Institute at the campus, to bring more qualified students from underrepresented groups to campus, and train them to become the future leaders in science and engineering.

非技术性：该职业奖由马萨诸塞大学阿默斯特分校材料研究部生物材料项目颁发，旨在开发能够以受控、可重复和经济的方式捕获人体组织特性的新型材料。它由 BioMaps 计划和 ENG/CBET/BBBE 计划的资金共同资助。目前，新药的开发是通过筛选数百种可能的候选药物来对抗塑料表面生长的癌细胞。显示出潜力的药物会在动物身上进行进一步测试，从零到少数候选药物都可以通过这个过程，然后将它们送往临床试验。在塑料表面的细胞中表现出成功的候选药物通常在临床试验中失败。总体而言，这个过程漫长且不划算。正在研究的生物材料具有潜在的用途，可用于了解癌细胞如何在模拟人体组织的环境中对药物做出反应，从而克服现有方法的一些缺点。 PI 计划通过该奖项为从高中到研究生的学生开发新的教育机会。高中生，尤其是女生，将在夏季在 PI 实验室接受培训，在那里这些学生可以学习如何进行细胞培养和 3D 打印技术，并观察细胞如何在不同材料表面上移动和生长。本科生将接受培训，创造新的途径来掌握自己的学习经验，并拥有自己的学习经验，从而形成可以在全国范围内使用的教育模块。在研究生阶段，重点将是从全国范围内代表性不足的群体中招募高能力的学生，成为下一个在材料和生物学领域工作的领先科学家。技术：细胞抵抗化疗的能力影响着全球的癌症患者。当前利用塑料多孔板的药物筛选技术的核心问题是它无法考虑细胞的天然材料微环境。该CAREER项目将采用变革性方法进行药物筛选，通过量化生物材料平台中癌细胞对药物的反应，模拟肿瘤微环境快速演变的材料特性，特别是由驻留间充质干细胞（MSC）不断重塑的材料微环境。该提案将使用高通量生物材料平台来确定三维基质硬度、整合素结合以及可溶性生长因子和细胞因子如何影响癌细胞对药物的反应。潜在的假设是，来自 MSC 重塑的细胞外基质 (ECM) 的物理和生化信号会干扰小分子药物的功效，而针对 MSC，而不是癌细胞，可以阻止这种耐药性。该提案的结果将改变我们对物理环境在干扰小分子药物中所起作用的基本理解。 PI 将利用职业资助来增加三个层次的生物工程教育机会：高中、本科生和研究生。 PI 已经在马萨诸塞大学阿默斯特分校创建了一个新的夏季实验室项目，向高中生教授细胞培养和先进的显微镜技术。在接下来的几年里，PI 计划为本科生创建新的教育模块，专门针对自主学习技巧以及在课堂上培养创造力和团队合作精神。此外，PI 计划与校园多样性研究所合作，在全国范围内扩大招聘力度，将更多来自弱势群体的合格学生引入校园，并培训他们成为未来的科学和工程领域的领导者。