CAREER: Engineering and design of multifunctional protein inhibitors to understand and control complex biological systems

Biological systems are complex. Layers of reaction and control networks come together to create cellular metabolism. Proteins participate in reaction and control networks. As such, regulating proteins is central to manipulating metabolism. Some proteins serve multiple functions. This makes them interesting targets for modification. The objective of the project is to design multifunctional proteins that can simultaneously affect different pathways. The pathways of interest are related to production of a gel called the extracellular matrix (ECM) that buffers cells from their surroundings. The ECM can also prevent drugs from reaching their target, in the case of tumor cells, for example, which makes understanding the properties of the ECM especially important. Developing educational modules that lean heavily on visual outputs and presenting them to K-12 students will provide an interesting opportunity for interactive learning in a gaming environment. Summer camps and research opportunities for high school students and undergraduates will be employed to promote engagement in STEM careers. Tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that play a critical role in regulating the extracellular matrix (ECM). TIMPs interact with various ECM components and display a range of binding affinity and selectivity. This versatility makes TIMPs great protein scaffolds for regulating complex biological systems and protein networks within the ECM. The main project objective is to engineer and design new multifunctional TIMPs capable of selectively targeting multiple ECM proteins. Directed evolution and high- throughput screening, combined with computational approaches, will address current gaps in protein engineering and design of multifunctional protein inhibitors. Further, the multifunctional inhibitory roles of TIMPs and their engineered variants will be tested in biochemical and cell-based assays to better understand their regulatory functions in cellular processes. These engineered multifunctional protein scaffolds will shed light on the regulation of complex biological systems in ECM. This project is jointly funded by the Established Program to Stimulate Competitive Research (EPSCoR) and the Cellular and Biochemical Engineering Program (ENG/CBET). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.