CAREER: Engineering Extracellular Matrix Ligands for Macrophage Control

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Macrophages are immune cells that can direct wound healing by adopting functional states that range from pro-inflammatory (bad) to pro-tissue healing (good). To change their functional state, macrophages receive signals from their environment/extracellular matrix (ECM). One of the ways the ECM can direct macrophage function is through integrins. Integrins are receptors found on macrophage membranes, and their associated ligands (molecules that can bind to the receptors) are found throughout the ECM. The ECM integrin receptor-ligand pair can determine the macrophage functional state. Currently, there are limited strategies to understand the fundamental relationship between ECM ligands and macrophage integrin receptors. In this CAREER project, the investigator will combine ECM ligands with peptide polymer chemistry to design biomaterial tools for investigating the influence of ECM ligands on macrophage function. The proposed program will increase fundamental understanding of how ECM ligands inform macrophage function by introducing biomaterial tools to quantify ECM ligand influence. Education and outreach activities are integrated with the proposed research and involve introducing a biomaterials business project plan for undergraduate students, developing a workshop for biomaterial career exposure to historically excluded students, and extending biomaterial projects for middle school students.Macrophage immune cells determine tissue homeostasis, wound healing, and tissue regeneration through signals from their microenvironment. The investigator’s long-term research goal is to understand how extracellular matrix (ECM) composition directs macrophage function. In support of this goal, this CAREER project focuses on developing polyethylene glycol-based biomaterial tools with known peptide-derived ECM ligands to quantify integrin ligand-receptor influence on macrophage activation. While it is understood how some cues direct macrophage function, as a field it is not understood how the extracellular matrix (ECM) directs macrophage function. Existing experimental systems designed to investigate macrophage function in the ECM are limited due to lack of control over incorporation of ECM ligands. The tools developed in this project will overcome this limitation. Studies are designed to test the central hypothesis that ECM-derived ligands from collagen, laminin, and fibronectin direct macrophage activation either towards a pro-inflammatory state or towards a pro-tissue healing state. Leveraging polymer chemistry and known ECM ligands, the proposed work comprises three research objectives: 1) quantifying integrin ligands influence on macrophage function via three-dimensional peptide screening, 2) designing combinatorial ECM ligand biomaterials to quantify ECM niche impact on macrophage function; and 3) quantifying the influence of age on human-donor macrophage function via combinatorial ECM ligand biomaterials. To successfully complete these aims, techniques established in the investigator’s lab will be employed for polymer-peptide conjugation, hydrogel formulation, mechanical assessments, and soluble stimulation of macrophages in a three-dimensional biomaterial. Molecular evaluations of macrophage function will include secretome analysis, immunocytochemistry, and interrogation of genetic expression alterations as a result of interaction with each ECM ligand. Completion of the tasks set forth will lay the foundation understanding how ECM ligands direct macrophage function through design of biomaterial tools.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.