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.

我特别有兴趣在工程，化学和生物学的交集上追求好奇心驱动的思想。我们问“如果呢？”研究中的问题是为了找到会影响加拿大社会和经济的创新解决方案。在工程生物化学系统中，我建议利用蛋白质的力量，并具有可控释放和开拓性3D细胞培养设计的变革性策略，以指导细胞命运。 亲和力释放通常由本机相互作用控制，但是此方法本质上受到限制，通常不可调节。我们发明了可调蛋白释放策略（在科学上发表），但这需要融合蛋白表达。现在，我们提出了一个全新的系统，以确定每个感兴趣的蛋白质的特定结合伙伴，并将这些伴侣固定在新的水凝胶递送工具上，从而基于特定的正交相互作用，从而产生了亲和力释放系统。使用该系统，我们预计以不同的速率交付多种蛋白质，并建议开发数学模型以预测和优化释放。从聚合物纳米/微粒中控制蛋白质的释放受过程本身的限制，可释放出少量蛋白质和较差的生物活性。通过利用静电相互作用，我们发明了从带负电荷的纳米颗粒（在科学进展中发表）中发明了带正电蛋白的未封装蛋白质释放。现在，我们建议使用瞬态显示电荷显示的平台策略，以使用zwitterionic聚合物和数学建模来控制释放，以理解和预测释放。模仿细胞微环境是理解细胞命运的关键，这在常规的2-D培养物上固有地限制。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。我们建议将新型的3D水凝胶与定义的生化和机械性能（包括瞬态蛋白梯度）合成，以更好地了解细胞外基质如何​​影响细胞侵袭，生长和命运。通过区分健康和癌细胞的系统，我们有机会研究专门抑制入侵的策略。研究生和博士后研究员将提高知识并获得对加拿大创新经济至关重要的领域的宝贵经验：聚合物化学，合成生物学，蛋白质释放，计算建模，工程设计。 HQP中的公平，多样性和包容是我实验室的基石。在整个职业生涯中，我追求并保持了种族多样性和同等数量的男女。在此，HQP将通过我设计的特定程序和组织结构学习创造性地思考。他们在我的实验室中的经验将通过全球的多学科合作来丰富。