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.

项目概要 中性粒细胞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，并在炎症的发生和进展中发挥重要作用 回复。然而，一旦病原体被清除，中性粒细胞的去除至关重要，以避免长时间的感染。 避免炎症，避免对周围组织造成损伤。细胞凋亡对于中性粒细胞至关重要 功能关闭、迁移的中性粒细胞的去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，可储存 血小板激活后释放大量生物活性蛋白，参与多种功能 生理过程，包括调节炎症反应。该提案的目标是开发一个 使用合成生物学的模块化平台技术重新编程多能干细胞以生产 用于治疗的工程血小板。为此，我们建议利用固有存储， 血小板的贩运和释放能力，以构建可以调节和主动终止的运载工具 中性粒细胞功能。