CAREER: Mechanisms of Drug Resistance in a Responsive Biomaterial Platform

非技术：这个由材料研究部的生物材料项目授予马萨诸塞大学阿默斯特分校的职业奖项是开发能够以受控、可重复和经济的方式捕捉人体组织特性的新型材料。它是由生物地图计划和ENG/CBET/BBBE计划的资金共同资助的。目前，通过筛选数百种可能的候选药物来对抗生长在塑料表面的癌细胞，从而开发出新药。显示出潜力的药物将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一过程，然后它们被带到临床试验。在塑料表面的细胞中似乎成功的候选药物在临床试验中往往失败。总体而言，这一过程漫长，成本效益不高。正在研究的生物材料可能用于了解癌细胞在模拟人体组织的环境中对药物的反应，从而克服目前方法的一些缺点。通过这一奖项，PI计划为从高中到研究生水平的学生开发新的教育机会。高中生，特别是女性，将在夏季的几个月里在PI的实验室接受培训，这些学生可以在那里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的材料表面上移动和生长。本科生将接受培训，以创造新的途径来掌握他们的学习经验，从而产生可在全国范围内使用的教育模块。在研究生层面，重点将是从全国范围内代表性较低的群体中招募能力很强的学生，成为下一批在材料和生物学领域工作的顶尖科学家。技术：细胞抵抗化疗的能力影响着全球的癌症患者。目前使用塑料多孔板的药物筛选技术的一个核心问题是，它无法考虑细胞本身的材料微环境。这个职业项目将采用一种变革性的药物筛选方法，通过在模拟肿瘤微环境快速演变的材料特性的生物材料平台中量化癌细胞对药物的反应，特别是由常驻间充质干细胞(MSCs)不断重塑的材料微环境。这项提案将使用高通量生物材料平台来确定三维基质刚性、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)的物理和生化信号干扰了小分子药物的疗效，靶向MSCs，而不是癌细胞，可以阻止这种耐药性。这一提议的结果将改变我们对物理环境在干扰小分子药物方面所起作用的基本理解。PI将利用职业资助在三个层次增加生物工程的教育机会：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设立了一个新的暑期实验室项目，教授高中生细胞培养和高级显微镜技术。在接下来的几年里，PI计划为本科生创建新的教育模块，专门针对自我指导的学习技巧，并在课堂上培养创造力和团队合作。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工作，将更多来自代表性不足群体的合格学生带到校园，并将他们培养成未来的科学和工程领导者。

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.