CAREER: Defining How Extracellular Matrix Mechanics Regulate Neutrophil Function

About This Grant

This Faculty Early Career Development (CAREER) award will support research to study how a tissue’s mechanical properties regulate the innate immune response, specifically the population and function of what are termed neutrophils-a of innate immune cells. Neutrophil-a cells play a crucial role in clearing infections, healing wounds, and fighting disease. To perform these tasks, they must navigate complex tissues throughout the body. While the chemical signals that guide neutrophil function are well studied, how the mechanical properties of a tissue influence neutrophil function remains unclear. Understanding this relationship is important because neutrophil dysfunction is linked to diseases that also involve changes in tissue mechanics and include cancer, heart disease, fibrosis, and conditions such as aging. This research will explore how mechanical changes in the tissue affect neutrophil function at a basic level and could help us understand how these changes worsen disease outcomes. This project will also develop a basic curriculum designed to improve scientific literacy in immunology to enhance participation in public health initiatives through community-engaged outreach while improving retention and recruitment of underrepresented students in science and engineering using both real-world applications and inclusion in the curriculum development process. The research objective of this project is to define how matrix modulus, viscoelasticity, and dynamic tissue stiffening regulate neutrophil function in inflammation while determining how these mechanical features regulate the expression and secretion of inflammatory mediators in the tissue microenvironment. This will be accomplished through three research objectives. The first research objective will decouple viscoelasticity and stiffness to determine their individual role in modulating the neutrophil response. The second research objective will investigate the effect of dynamic tissue stiffening on the neutrophil response. The third research objective will identify genetic expression and secretion profiles that are altered in response to changes in mechanical properties. All objectives will use novel engineered collagen-alginate hydrogels in an inflammation-on-a-chip microfluidic device that recapitulates key features of the inflammatory microenvironment including a model blood vessel, a tunable extracellular matrix, primary human cells, and an inflammatory stimulus. Collectively, these results will establish mechanical features of the extracellular matrix as critical regulators of neutrophil function and broadly impact our understanding of innate immune cell regulation in healthy tissues and disease. Specifically, the results will provide mechanistic insight into how mechanical cues from the matrix regulate neutrophils providing targets for modulating their function in infection and disease. 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.