Synthetic circuits for therapeutic platelet production and immunomodulation

用于治疗性血小板生成和免疫调节的合成回路

• 批准号: 10745237
• 负责人: Tara Lynn Deans
• 金额: $ 46.45万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745237
• 关键词: Apoptosis; Behavior; Binding; Blood Cells; Blood Platelets; Cell Fate Control; Cell Therapy; Cells; Coagulation Process; Cytoplasmic Granules; Disease; Drug Delivery Systems; Emigrations; Engineering; Event; Excision; Gene Expression; Genetic; Goals; Harvest; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemostatic function; Immune; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Invaded; Learning; Link; Measures; Mediating; Medical Technology; Megakaryocytes; Membrane; Migration Assay; Molecular; Mutate; Neutrophil Infiltration; Operative Surgical Procedures; Pathogenicity; Pathway interactions; Perfusion; Pharmacologic Substance; Physiological Processes; Platelet Activation; Play; Pluripotent Stem Cells; Process; Production; Proteins; Reporter; Research; Resolution; Role; Secretory Vesicles; Signal Transduction; Site; Synthetic Genes; Therapeutic; Thrombin; Tissues; Transcription Coactivator; Transcription Repressor; Transcriptional Regulation; Tumor Necrosis Factor Ligand Superfamily Member 6; Vision; Work; angiogenesis; delivery vehicle; design; design,build,test; flexibility; gene network; hematopoietic differentiation; hematopoietic stem cell differentiation; immunoregulation; in vitro Assay; inflammatory modulation; microorganism; migration; neutrophil; non-Native; novel therapeutic intervention; pathogen; programs; recruit; response; stem cell differentiation; success; synthetic biology; technology platform; therapeutic evaluation; therapeutic gene; therapeutic protein; tissue injury; tool; trafficking; wound healing

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.

项目摘要 中性粒细胞被迅速募集到感染和损伤部位，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发挥重要作用， 反应然而，一旦病原体被清除，就必须去除中性粒细胞，以避免长时间的 以避免对周围组织造成伤害。细胞凋亡是中性粒细胞 功能性关闭、移走的中性粒细胞的清除以及炎症的及时解决。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、炎症和凝块形成。血小板自然充满分泌颗粒， 血小板活化后释放的大量生物活性蛋白质参与了多种 生理过程，包括调节炎症反应。该提案的目标是制定一个 模块化平台技术，利用合成生物学对多能干细胞进行重新编程， 用于治疗的工程血小板。为此，我们建议利用先天储存， 血小板的运输和释放能力，以构建可以调节和主动终止 中性粒细胞功能。