CAREER: A systems approach to create multiplexed microfluidics to study human immune cell dynamics

点击翻译按钮获取中文摘要

It is difficult to study the function of immune cells directly in a living person. As a solution, engineers use small microfluidic devices, also known as microphysiological systems, to simulate the conditions of health and disease in humans. This CAREER project will lead to the development of validated models of human inflammation in multiple tissue microenvironments. By mimicking the complex 3D microenvironments of tissues and organs, the models created will allow researchers to investigate the dynamic interactions between immune cells, signaling molecules, and pathogens (micoorganisms that cause disease). Complementary to microfluidic models, mathematical modeling offers a quantitative framework to understand the underlying mechanisms and dynamics of inflammation. By employing mathematical equations and computational simulations, researchers can design better human-based in vitro (in the lab) models and analyze cellular and molecular interactions involved in inflammation. These models aid in predicting and optimizing treatment outcomes, unraveling the complexity of chronic inflammation, and identifying potential interventions. The Investigator will integrate research with teaching through an interactive immunology virtual reality game that teaches how the immune system and vaccines work. This virtual reality learning module will be presented at the Institute of Electrical and Electronics Engineers (IEEE) conference and disseminated to the local community in a K-12 partnership with Dallas and Richardson Independent School Districts. The Investigator proposes a comprehensive strategy to recruit and retain underrepresented students and has served in several leadership roles in the Dallas community, including serving as a mentor for the Young Women In Science and Engineering Investigators (YWISEI) program and the George A. Jeffrey NanoExplorers Program at the high school level. The vision of the Investigator’s Lab in the next decade is to combine mathematical and multiplexed microfluidic experimental approaches into a unified and powerful tool to decipher the emergent properties governing immune cell differentiation and activation in response to the external microenvironment. Understanding the basic differences in immune cell function in different microenvironments is expected to shine light onto the mechanisms of end-organ-failure. Towards this vision, the goal of this CAREER project is to employ a systems immunology approach, integrating experimental data with computational modeling to unravel the dynamics of immune cell responses by pursuing the following objectives: (1) Creating a multiplexed-microenvironment chip that is informed by a quantitative framework (deterministic and stochastic spatiotemporal models and data analytics methods) for immune cell migration and neutrophil extracellular trap release (NETosis) in specific organoid microenvironments (lung, kidney, brain); (2) Validating the multiplexed organ microenvironments-on-a-chip and mathematical models by correlating time-lapse movies of in vitro immune cells phenotypes (migration and NETosis) with clinical outcomes (end-organ-failure) in pediatric patients before and after cardiac bypass surgery; and (3) Modulating the immune function on-chip with lipid mediators and novel chemotactic microparticles. The engineering tools developed in this project, can be applied not only clinically, but to study basic mechanisms and roles of immune cells in inflammatory disorders, infectious disease, and regenerative therapy.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.