CAREER: Phase-separating Membrane Materials for Efficient and Specific Molecular Delivery to Cells

职业：相分离膜材料，用于高效且特定的分子递送至细胞

• 批准号: 1352487
• 负责人: Jeanne Stachowiak
• 金额: $ 49.91万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1352487&HistoricalAwards=false
• 关键词: CAREER; Phase; separating; Membrane; Materials

Non-technical:This CAREER award by the Biomaterials program in the Division of Materials Research to University of Texas at Austin is to develop biomaterials for drug delivery system. From eliminating cancerous tumors to repairing damaged tissues, medicine frequently relies on our ability to direct multiple types of therapeutics to diseased cells, while sparing healthy cells from exposure. This project designs biomaterials that are capable of precisely recognizing diseased cells and efficiently delivering therapeutics to them. In particular, the materials developed in this work undergo a dramatic transformation from a non-interactive state to a highly interactive state when they recognize specific markers on the surfaces of diseased cells. This strategy will enable highly specific therapeutic delivery to diseased cells, increasing the capability and efficiency of pharmaceutical therapy while decreasing side effects. Furthermore, this work will create new opportunities to build a broad range of simple, man-made materials and systems that mimic the ability of living cells to sense and respond to changes in their environment. As part of the broader impact activities, this project plans to increase minority student participation in STEM, by inviting a diverse group of freshman students to contribute original ideas for the design of minimal 'cell-like' systems. Several students with promising ideas will be invited to try them out in the laboratory, providing them with a unique opportunity to solve real-world problems by combining creativity with critical thinking. By presenting the results of these design projects to local high school science classes, students will build confidence in their ability to succeed in STEM, while simultaneously inspiring the next generation of students to consider STEM careers.Technical:This CAREER award by the Biomaterials program in the Division of Materials Research to University of Texas at Austin is to develop biomaterials for drug delivery system to transport large macromolecular cargos such as genes and proteins efficiently and specifically across the cell's plasma membrane. In this project, the investigator will be mimicking a strategy used by cells to recognize one another -coupling of ligand-receptor binding to membrane biomaterials that phase separate when they recognize threshold levels of receptors on the surfaces of target cells. This award is cofunded by the Biotechnology, Biochemical, and Biomass Engineering program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems. This project will be addressing some of the challenges facing the drug delivery system of large macromolecular cargos efficiently and specifically to inside of the cell. This project will design and synthesize membrane-based biomaterials using synthetic and phase separating liposomes. Synthetic polysomes will be designed with careful tuning the density of ternary lipid mixture ligands and fusion proteins on its surface. During cell-cell recognition and fusion, ligand-receptor interactions alter the local membrane composition, causing cellular membranes to undergo a highly localized phase separation that dramatically concentrates ligands and receptors, strengthening cell-cell contacts. Following these contacts, these membrane biomaterials phase separate when they recognize threshold levels of receptors on the surfaces of target cells, driving membrane fusion and delivery of molecular cargos to the cellular cytoplasm. Furthermore, these materials provide new tools for designing 'cell-like' systems that sense and respond to environmental changes. Drawing on this toolkit, educational efforts will center on a new course that will challenge freshman in non-STEM majors to come up with ideas for 'simple biological machines'. This unique project will invite a diverse group of students to share in the excitement of scientific innovation while many are still choosing their academic major and future career, broadening participation in science on our campus.

非技术性：德克萨斯大学奥斯汀分校材料研究部生物材料项目颁发的这项职业奖旨在开发用于药物输送系统的生物材料。 从消除癌性肿瘤到修复受损组织，医学经常依赖于我们将多种类型的治疗方法引导到患病细胞的能力，同时使健康细胞免受暴露。该项目设计的生物材料能够精确识别病变细胞并有效地向其提供治疗。特别是，在这项工作中开发的材料在识别病变细胞表面的特定标记时，经历了从非相互作用状态到高度相互作用状态的戏剧性转变。这种策略将使高度特异性的治疗药物输送到病变细胞，提高药物治疗的能力和效率，同时减少副作用。 此外，这项工作将创造新的机会，建立一个广泛的简单的人造材料和系统，模仿活细胞的能力，以感知和响应其环境的变化。作为更广泛的影响活动的一部分，该项目计划通过邀请不同群体的大一学生为最小的“细胞样”系统的设计贡献原创想法，来增加少数民族学生对STEM的参与。几个有前途的想法的学生将被邀请在实验室里尝试，为他们提供一个独特的机会，通过结合创造力和批判性思维来解决现实世界的问题。通过向当地高中理科班展示这些设计项目的成果，学生们将树立在STEM领域取得成功的信心，同时激发下一代学生考虑STEM职业。技术：该职业奖由德克萨斯大学奥斯汀分校材料研究部生物材料项目授予，旨在开发用于药物输送系统的生物材料，以有效并特异性地将基因和蛋白质等大分子货物输送到细胞质膜上。在这个项目中，研究人员将模仿细胞相互识别所使用的策略-将配体-受体结合偶联到膜生物材料上，当它们识别靶细胞表面上受体的阈值水平时，膜生物材料发生相分离。该奖项由化学，生物工程，环境和运输系统部门的生物技术，生物化学和生物质工程项目共同资助。该项目将解决大型大分子货物的药物递送系统所面临的一些挑战，有效地并具体到细胞内部。本计画将利用合成脂质体及相分离脂质体来设计及合成膜基生物材料。合成的多聚核糖体将通过仔细调整其表面上的三元脂质混合物配体和融合蛋白的密度来设计。在细胞-细胞识别和融合过程中，配体-受体相互作用改变了局部膜组成，导致细胞膜发生高度局部化的相分离，从而显著浓缩配体和受体，加强细胞-细胞接触。在这些接触之后，当这些膜生物材料识别靶细胞表面上的阈值水平的受体时，它们相分离，从而驱动膜融合并将分子货物递送至细胞质。此外，这些材料为设计“细胞样”系统提供了新的工具，这些系统可以感知和响应环境变化。利用这个工具包，教育工作将集中在一个新的课程，这将挑战非STEM专业的新生想出“简单的生物机器”的想法。这个独特的项目将邀请不同群体的学生分享科学创新的兴奋，而许多人仍在选择他们的学术专业和未来的职业，扩大在我们的校园科学参与。