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Creating Smart Biomaterials using Engineered Bacteria that Cooperatively Reprogram Mammalian Cells

使用协同重编程哺乳动物细胞的工程细菌创造智能生物材料

基本信息

批准号：
1709238
负责人：
Warren Ruder
金额：
$ 33.84万
依托单位：
University of Pittsburgh
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1709238&HistoricalAwards=false
关键词：
Creating Smart Biomaterials using Engineered

项目摘要

NON-TECHNICAL ABSTRACTAn ability to reprogram the function of mammalian cells is critical for exploring the scientific underpinnings of cell behavior as well as improving human health. This effort will result in the development of smart biomaterials and experimental systems made up of microparticles carrying engineered bacteria. These hybrid, living-nonliving biomaterials will be used as a tool to reprogram mammalian cell signaling. One advantage of an extendable synthetic biomaterials approach that uses engineered bacteria to regulate mammalian calcium signaling could be the abrogation of the need to directly alter mammalian cells to reprogram their behavior. Thus, the need for vectors such as viruses or the creation of transgenic animal models could be reduced. For this effort, bacteria-bound microparticles will be developed that can deliver synthetic genetic components to mammalian cells and reprogram calcium signaling. Calcium signaling is a ubiquitous system that effects cells ranging from nerves to the cells that line the gut, and controls both slow and fast cellular processes. Next, these particles will be made into ?smart? biomaterials as their living component ? the bacteria ? will be engineered with an ability to collaborate and collectively determine when to transmit genetic components to mammalian cells. Finally, mathematical modeling and computational simulation will be used to explore calcium signaling dynamics in mammalian cells in order to determine when alterations will cause the most significant changes in cell signaling dynamics. The smart biomaterials will then be used to reprogram this signaling. In addition, this effort will be integrated with the development of multiple teaching modules for a bioengineering summer camp, and the final curriculum will be widely disseminated to the broader scientific and educational community.TECHNICAL ABSTRACTThis effort will result in the creation of smart biomaterials that link to engineered intracellular networks necessary for bacteria to cooperatively invade and then reprogram calcium signaling in mammalian cells. First, a synthetic component will be built to enable engineered bacteria to covalently bond to microparticles to create smart biosensing materials that target specific mammalian cell surface markers. Second, different bacterial lines will be programmed with engineered gene circuits that enable them to cooperatively recognize each other and then activate mammalian cell invasion capabilities. This cooperation further ensures that only specific mammalian cells are targeted. Finally, both the synthetic bonding and the cooperative invasion circuitry will be used to reprogram calcium signaling in mammalian cells. Invading bacteria will use RNA interference to alter the dynamics of calcium signaling by knocking down expression of calcium pathway enzymes. Selection of these target enzymes will be informed by modeling of single cell calcium dynamics. This effort will combine recent advances in engineered cellular invasion, mammalian synthetic biology, cell surface display, and engineered quorum sensing to create bacteria-laden, smart biomaterials that reprogram mammalian cells. The proposed effort includes research to advance discovery and understanding in the field of smart biomaterials while also promoting teaching, training, and learning through the development of a new activities targeted toward high school students.

非技术摘要重新编程哺乳动物细胞功能的能力对于探索细胞行为的科学基础以及改善人类健康至关重要。这一努力将导致智能生物材料和实验系统的发展，这些系统由携带工程细菌的微粒组成。这些混合的、有生命的非生命生物材料将被用作重新编程哺乳动物细胞信号的工具。使用工程化细菌调节哺乳动物钙信号传导的可扩展合成生物材料方法的一个优点可能是消除了直接改变哺乳动物细胞以重新编程其行为的需要。因此，可以减少对载体如病毒或建立转基因动物模型的需要。为了这项工作，将开发细菌结合的微粒，可以将合成的遗传成分传递到哺乳动物细胞并重新编程钙信号。钙信号传导是一个无处不在的系统，影响从神经到肠道细胞的细胞，并控制缓慢和快速的细胞过程。接下来，这些颗粒会被制成？聪明吗生物材料作为其生命成分？细菌？将被改造成具有合作能力，并共同决定何时将遗传成分传递给哺乳动物细胞。最后，数学建模和计算机模拟将用于探索哺乳动物细胞中的钙信号动力学，以确定何时改变将导致细胞信号动力学中最显着的变化。然后，智能生物材料将用于重新编程这种信号。此外，这一努力将与生物工程夏令营的多个教学模块的开发相结合，最终的课程将被广泛传播到更广泛的科学和教育界。技术摘要这一努力将导致智能生物材料的创建，链接到工程细胞内网络所必需的细菌合作入侵，然后重新编程哺乳动物细胞中的钙信号。首先，将构建一种合成组件，使工程菌能够共价键合到微粒上，以创建针对特定哺乳动物细胞表面标记的智能生物传感材料。第二，不同的细菌系将被设计基因电路，使它们能够合作识别彼此，然后激活哺乳动物细胞入侵能力。这种合作进一步确保了仅针对特定的哺乳动物细胞。最后，合成键合和合作入侵电路都将用于重新编程哺乳动物细胞中的钙信号。入侵细菌将使用RNA干扰通过敲低钙途径酶的表达来改变钙信号传导的动力学。这些靶酶的选择将通过对单细胞钙动力学的建模来了解。这项工作将结合联合收割机在工程细胞入侵，哺乳动物合成生物学，细胞表面展示，和工程群体感应的最新进展，创造细菌负载，智能生物材料，重新编程哺乳动物细胞。拟议的努力包括研究，以推进智能生物材料领域的发现和理解，同时通过开发针对高中生的新活动来促进教学，培训和学习。