Project Summary Neutrophils are rapidly recruited to the sites of infection and injury to form the first line of defense against invading pathogens or tissue injury, and play a prominent role in the initiation and progression of the inflammatory response. However, once the pathogens are cleared, it is critical for neutrophils to be removed to avoid prolonged inflammation and to avoid inflicting damage to the surrounding tissue. Apoptosis is essential for neutrophil functional shutdown, removal of emigrated neutrophils, and the timely resolution of inflammation. Platelets are anucleate blood cells that circulate throughout the body and play an important role in hemostasis, wound healing, angiogenesis, inflammation, and clot formation. Platelets are naturally filled with secretory granules that store large amounts of bioactive proteins that are released following platelet activation to participate in a myriad of physiological processes, including modulating inflammatory responses. The goal of this proposal is to develop a modular platform technology using synthetic biology to reprogram pluripotent stem cells for the production of engineered platelets for therapeutic treatments. Towards this end, we propose to capitalize on the innate storage, trafficking, and release capabilities of platelets to build delivery vehicles that can modulate and actively terminate neutrophil function.

Project Narrative In this proposal, we aim to use synthetic biology approaches to engineer synthetic gene networks to create engineered platelets for immunomodulation. The genetic tools build in this proposed work will have a broad yet significant impact on inflammatory disease treatments.