Engineering Biochemical Systems

工程生化系统

• 批准号: RGPIN-2019-06933
• 负责人: Shoichet, Molly
• 金额: $ 6.56万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=692397
• 关键词: Engineering; Biochemical; Systems

I am particularly interested in pursuing curiosity-driven ideas at the intersection of engineering, chemistry and biology. We ask the “what if?” questions in research to find innovative solutions that will impact Canada's society and economy. In Engineering Biochemical Systems, I propose to harness the power of proteins with both transformative strategies for controlled release and pioneering 3D cell culture designs to guide cell fate. ******Affinity release is typically controlled by native interactions, but this method is inherently limited and typically not tunable. We invented a tunable protein release strategy (published in Science), but this requires fusion protein expression. We now propose an entirely new system to identify specific binding partners for each protein of interest and immobilize these partners on a new hydrogel delivery vehicle, resulting in an affinity release system based on specific orthogonal interactions. With this system, we anticipate delivering multiple proteins at different rates, simultaneously, and propose to develop the mathematical model to predict and optimize release.******Controlling protein release from polymeric nano/microparticles is limited by the process itself to very small amounts of protein released and poor bioactivity. By taking advantage of electrostatic interactions, we invented un-encapsulated protein release of positively charged proteins from negatively charged nanoparticles (published in Science Advances). We now propose a platform strategy using transient display of charge to control release using zwitterionic polymers and mathematical modelling to understand and predict release.******Mimicking the cellular microenvironment is key to understanding cell fate, which is inherently limited by conventional 2-D culture. We invented a series of hydrogel chemistry strategies that provide us with the tools required to ask key questions in cell biology. We propose to synthesize novel 3D hydrogels with defined biochemical and mechanical properties, including transient protein gradients, to better understand how the extracellular matrix influences cell invasion, growth and fate. With systems that differentiate between healthy and cancer cells, we have the opportunity to investigate strategies that specifically inhibit invasion.******Graduate students and post-doctoral fellows will advance knowledge and gain valuable experience in fields of critical importance to Canada's innovation economy: polymer chemistry, synthetic biology, protein release, computational modeling, engineering design. Equity, diversity and inclusion in HQP are the cornerstone of my laboratory. I have pursued and maintained ethnic diversity and equal numbers of women and men throughout my entire career. Herein, HQP will learn to think creatively and independently through specific programs and organizational structures that I have designed. Their experience in my laboratory will be enriched through multi-disciplinary collaborations worldwide. **

我特别感兴趣的是在工程学、化学和生物学的交叉点上追求好奇心驱动的想法。我们会问“如果呢？”研究中的问题，以找到将影响加拿大社会和经济的创新解决方案。在工程生化系统中，我建议利用蛋白质的力量，既有控制释放的变革性策略，也有开创性的3D细胞培养设计来指导细胞命运。*亲和力释放通常由本机交互控制，但此方法固有限制，通常不可调优。我们发明了一种可调节的蛋白质释放策略(发表在《科学》杂志上)，但这需要融合蛋白质的表达。我们现在提出了一种全新的系统来识别每个感兴趣的蛋白质的特定结合伙伴，并将这些伙伴固定在新的水凝胶输送载体上，从而产生基于特定正交相互作用的亲和释放系统。利用该系统，我们预计将以不同的速率同时输送多个蛋白质，并建议开发数学模型来预测和优化释放。*控制聚合物纳米/微米颗粒中的蛋白质释放受到该过程本身的限制，因为释放的蛋白质量很少且生物活性很差。通过利用静电相互作用，我们发明了从带负电荷的纳米粒子中释放带正电荷的蛋白质的未被包裹的蛋白质(发表在《科学进展》上)。我们现在提出一种平台策略，利用两性离子聚合物的瞬时电荷显示来控制释放，并通过数学建模来理解和预测释放。*模拟细胞微环境是理解细胞命运的关键，而传统的二维培养天生就限制了细胞的命运。我们发明了一系列水凝胶化学策略，为我们提供了在细胞生物学中提出关键问题所需的工具。为了更好地理解细胞外基质如何影响细胞的侵袭、生长和命运，我们建议合成具有明确的生化和力学性质的新型3D水凝胶，包括瞬时蛋白质梯度。有了区分健康细胞和癌细胞的系统，我们有机会研究具体抑制入侵的策略。*研究生和博士后研究员将在对加拿大创新经济至关重要的领域增进知识并获得宝贵经验：聚合物化学、合成生物学、蛋白质释放、计算建模、工程设计。公平、多样性和对HQP的包容是我实验室的基石。在我的整个职业生涯中，我一直追求和维护种族多样性和同等数量的男女。在这里，HQP将通过我设计的具体计划和组织结构来学习创造性和独立思考。他们在我的实验室的经验将通过世界各地的多学科合作得到丰富。**