Synthetic circuits for therapeutic platelet production and immunomodulation

项目摘要 中性粒细胞被迅速招募到感染和损伤部位，形成抵御入侵的第一道防线。 病原体或组织损伤，并在炎症的发生和发展中起着突出作用 回应。然而，一旦病原体被清除，去除中性粒细胞以避免延长时间是至关重要的。 发炎，避免对周围组织造成损害。细胞凋亡对中性粒细胞是必不可少的 关闭功能，清除迁出的中性粒细胞，及时消退炎症。血小板是 无核血细胞在全身循环，在止血、伤口愈合、 血管生成、炎症和血栓形成。血小板自然充满了分泌颗粒，可以储存 在血小板激活后释放的大量生物活性蛋白参与了无数 生理过程，包括调节炎症反应。这项提议的目标是开发一种 模块化平台技术，使用合成生物学对多潜能干细胞进行重新编程，以生产 用于治疗的人造血小板。为此，我们建议利用先天的存储能力， 贩运和释放血小板的能力，以建立可以调节和主动终止的递送工具 中性粒细胞功能。

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.