CAREER: Fundamental Understanding of Self-Assembly by Peptide-Polymer Conjugates in Creating Functional Biomaterials from Multiscale Simulations

职业：通过多尺度模拟创建功能性生物材料时对肽-聚合物缀合物自组装的基本理解

• 批准号: 1554508
• 负责人: Hung Nguyen
• 金额: $ 50.85万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1554508&HistoricalAwards=false
• 关键词: CAREER; Fundamental; Understanding; Self; Assembly

Proposal: 1554508PI: Nguyen, Hung D.Dynamic nanomaterials that can change their shape and structure in response to environmental stimuli hold promise to revolutionize medicine and biotechnology. However, the current discovery process of such smart materials is slow and often serendipitous due to the enormously large design space and lack of systematic knowledge as well as predictive models. Indeed, a quantitative understanding of their self-assembly and disassembly processes, and how the solution condition and chemical structure govern their morphological transition, has remained elusive. To tackle these challenges and harness the full potential of smart materials, the PIs will build an integrated platform of computer-aided design using peptide-polymer conjugates by performing molecular simulations in collaboration with experimentalists in facilitating rapid development of novel stimuli-responsive nanomaterials for different biomedical applications in cancer and gene therapy. The proposed research will provide timely and invaluable tools and knowledge to move the community towards expedited discovery of smart materials that help improve lives. Specifically, the valuable insights gained from the simulation studies could lead to the development of a cancer-specific diagnostic agent and targeted gene delivery system.The specific objectives of the proposed CAREER research program are: 1) elucidate the sequence-structure-property relationships in solution for de novo design of PEG-conjugated peptide amphiphiles as delivery vehicles of drugs or bioimaging agents; 2) examine the crowding effects of the blood serum and in vivo conditions on stimuli-responsive self-assembly by peptide amphiphiles; 3) understand the relationship between peptide-polymer conjugate sequence and structure of siRNA complexes and mechanisms of siRNA complexation by different conjugates for gene delivery; and 4) investigate the mechanisms of intracellular trafficking of siRNA complexes and siRNA disassembly by peptide-polymer conjugates. By integrating multi-scale modeling techniques, the proposed platform will innovate and accelerate the materials discovery process in two transformative ways. First, the development of new models and simulations tools will push the boundary of multi-scale modeling and pave the way for computer-aided design of novel biomaterials. Second, the integrated in silico and in vitro and in vivo studies of sequence-structure-properties relationships and assembly/disassembly processes will generate novel, systematic knowledge that will be applied to design novel stimuli-responsive delivery vehicles for improved pharmaco-kinetic properties. To broaden the impact of the planned research, the PI will integrate research into the undergraduate curricula by developing a new course on biomaterial design and offering research opportunities for undergraduate students. Furthermore, the PI will launch a summer research program for high school students to perform simple simulations in his laboratory for one week and will play an active role in training middle and high school teachers to integrate engineering concepts and hands-on experiential learning methodologies into their science curriculum.

提案：1554508PI：nguyen，悬挂的d.动态纳米材料，可以改变其形状和结构，以响应环境刺激，这有望改变医学和生物技术。但是，由于设计空间庞大，缺乏系统知识和预测模型，此类智能材料的当前发现过程是缓慢的，通常是偶然的。确实，对他们的自组装和拆卸过程的定量理解，以及解决方案条件和化学结构如何控制其形态过渡，这仍然是难以捉摸的。为了应对这些挑战并利用智能材料的全部潜力，PI将通过与实验者合作进行分子模拟，在促进新型刺激性刺激性纳米材料的快速开发方面，通过与实验者合作进行分子仿真，建立一个计算机辅助设计的集成平台。拟议的研究将提供及时，宝贵的工具和知识，以使社区迅速发现有助于改善生活的智能材料。具体而言，从模拟研究中获得的有价值的见解可能会导致癌症特异性诊断剂和靶向基因输送系统的发展。拟议的职业研究计划的特定目标是：1）阐明序列结构 - 结构 - 实质性的关系，用于DE NOVO设计的peg固定肽疗法或送货药物的pego e Novo设计，或者2）检查血清血清和体内条件对肽两亲物的刺激自我组装的拥挤影响； 3）了解肽聚合物偶联物序列与siRNA复合物的结构与不同偶联物的siRNA络合机理的结构之间的关系； 4）研究肽 - 聚合物偶联物的siRNA复合物和siRNA拆卸的细胞内运输机制。通过集成多尺度建模技术，提出的平台将以两种变革性的方式创新和加速材料发现过程。首先，开发新的模型和仿真工具将推动多尺度建模的边界，并为新型生物材料的计算机辅助设计铺平道路。其次，集成在硅和体外和体内研究序列结构 - 培养物关系以及组装/拆卸过程的体内研究将产生新颖的，系统的知识，这些知识将用于设计新型的刺激性反应性递送工具，以改善药物型的运动特性。为了扩大计划研究的影响，PI将通过开发有关生物材料设计的新课程并为本科生提供研究机会来整合本科课程的研究。此外，PI将启动一项夏季研究计划，供高中生在其实验室中进行一个星期的简单模拟，并将在培训中学和高中教师中发挥积极作用，以将工程概念和动手的经验学习方法整合到其科学课程中。