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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739194
• 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.

我对在工程、化学和生物学的交叉领域追求好奇心驱动的想法特别感兴趣。我们问“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，我建议通过控制释放的变革策略和开创性的 3D 细胞培养设计来利用蛋白质的力量来指导细胞命运。 亲和力释放通常由本机交互控制，但这种方法本质上是有限的，并且通常不可调节。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），但这需要融合蛋白表达。我们现在提出了一种全新的系统来识别每种感兴趣的蛋白质的特异性结合伙伴，并将这些伙伴固定在新的水凝胶递送载体上，从而产生基于特定正交相互作用的亲和力释放系统。通过该系统，我们预计以不同的速率同时释放多种蛋白质，并建议开发数学模型来预测和优化释放。控制聚合物纳米/微粒中的蛋白质释放受到过程本身的限制，释放的蛋白质量非常小且生物活性差。通过利用静电相互作用，我们发明了从带负电的纳米颗粒中释放带正电的蛋白质的未封装蛋白质（发表在《科学进展》上）。我们现在提出了一种平台策略，使用电荷瞬态显示来控制释放，使用两性离子聚合物和数学模型来理解和预测释放。模拟细胞微环境是理解细胞命运的关键，这本质上受到传统二维培养的限制。我们发明了一系列水凝胶化学策略，为我们提供了提出细胞生物学关键问题所需的工具。我们建议合成具有明确的生化和机械特性（包括瞬时蛋白质梯度）的新型 3D 水凝胶，以更好地了解细胞外基质如何​​影响细胞侵袭、生长和命运。借助区分健康细胞和癌细胞的系统，我们有机会研究特异性抑制入侵的策略。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的经验：高分子化学、合成生物学、蛋白质释放、计算建模、工程设计。 HQP 的公平、多样性和包容性是我实验室的基石。在我的整个职业生涯中，我一直追求并保持种族多样性以及男女人数平等。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的思考。他们在我实验室的经验将通过全球多学科合作得到丰富。