Project 2 Endothelial Cell-Derived Extracellular Vesicles for Mitigation of the Hematopoietic Acute Radiation Syndrome

项目2 内皮细胞来源的细胞外囊泡用于缓解造血急性辐射综合征

• 批准号: 10693902
• 负责人: Phuong Linh Doan
• 金额: $ 40.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693902
• 关键词: Acceleration; Allogenic; Animals; Biological; Biological Assay; Bone Marrow; Cell Communication; Cell Proliferation; Cell Survival; Cells; Cessation of life; Clinical; Clinical Research; Communication; Cryopreservation; Data; Development; Devices; Disasters; Dose; Endothelial Cells; Endothelium; Engraftment; Extracellular Matrix; Family; Future; Gastrointestinal Injury; Goals; Granulocyte Colony-Stimulating Factor; Hematology; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Homing; Hour; Human; IL3 Gene; Immune Tolerance; Infection; Intestines; Ionizing radiation; Life; Marrow; Mass Spectrum Analysis; Measures; Mediating; Medical center; Mus; Myelosuppression; Natural regeneration; Nuclear; Nuclear Accidents; Nucleic Acids; Organ; Organoids; Pharmaceutical Preparations; Physiological; Protein Analysis; Protein Family; Protein Secretion; Proteins; Public Health; Publications; Radiation; Radiation Injuries; Radiation Protection; Radiation Toxicity; Radiation exposure; Radiation therapy; Recombinant Proteins; Recovery; Refractory; Regenerative capacity; Research; Risk; Schedule; Signal Transduction; Source; Stem cell transplant; Terrorism; Testing; Tissue Inhibitor of Metalloproteinases; Transplantation; Umbilical Cord Blood; Vascular Endothelial Cell; chemotherapy; comparison control; cytokine; exosome; extracellular vesicles; gastrointestinal; gastrointestinal system; irradiation; mass casualty; medical countermeasure; microvesicles; mouse model; novel; permissiveness; radiation mitigation; radiation mitigator; radiation response; regenerative; repaired; response; stem cell expansion; stem cell self renewal; translational applications; weapons

ABSTRACT The misuse of ionizing radiation or nuclear devices as weapons of terrorism has been recognized as a major U.S. public health threat. The greatest risk to these victims of radiation exposure is the hematopoietic acute radiation syndrome (H-ARS), which results in life-threatening complications such as infections and refractory bleeding. Specific therapies directed at H-ARS to accelerate hematopoietic regeneration following radiation injury have been few. Since marrow endothelial cells can govern hematologic recovery after irradiation without homing to the bone marrow, endothelial cells can mediate their radioprotective effects through elaboration of hematopoietic cytokines or soluble factors. Another mechanism of cellular communication is through transfer of proteins and nucleic materials via secretion of extracellular vesicles (EVs). EVs range in size from 100-250 nm and bear both nucleic acids and proteins that have potential to regulate neighboring cells. We hypothesize that ECs exert their regenerative effects through EVs. We have shown that treatment of irradiated hematopoietic stem/progenitor cells with either syngeneic or allogeneic EVs from genetically distinct mice results in comparable expansion of the stem cell pool, suggesting they could be immunologically tolerant. Compared to control mice treated with granulocyte colony stimulating factor (G-CSF), it is possible that EVs are at least comparable and are likely superior to G-CSF for prolonging survival after lethal-dose irradiation. Our overriding goal is to demonstrate the radiotherapeutic capacity of EVs. In doing so, we will develop a cellular-based therapy for H-ARS with potential for off-the-shelf delivery to victims in the setting of a mass casualty disaster.

摘要 滥用电离辐射或核装置作为恐怖主义武器已被认为是一种 美国公共卫生的重大威胁。对这些辐射受害者来说，最大的风险是造血系统 急性辐射综合征（H-ARS），导致危及生命的并发症，如感染和 顽固性出血针对H-ARS的特异性治疗，以加速以下造血再生： 辐射损伤很少。由于骨髓内皮细胞可以控制血液恢复后， 辐射而不归巢到骨髓，内皮细胞可以介导其辐射防护作用 通过造血细胞因子或可溶性因子的加工。另一种细胞机制 通讯是通过细胞外囊泡分泌的蛋白质和核酸物质的转移 （电动汽车）。EV的大小范围为100-250 nm，并且携带核酸和蛋白质，这些核酸和蛋白质具有潜在的 调节邻近的细胞。我们假设EC通过EV发挥其再生作用。我们有 显示用同基因或同种异体EV处理经辐射的造血干/祖细胞 从遗传上不同的小鼠中提取的干细胞导致干细胞库的相当扩增，这表明它们可能是 免疫耐受与用粒细胞集落刺激因子（G-CSF）处理的对照小鼠相比， EV可能至少与G-CSF相当，并且可能上级G-CSF， 致死剂量辐照我们的首要目标是展示电动汽车的辐射能力。在这样做时， 我们将为H-ARS开发一种基于细胞的治疗方法， 造成大规模伤亡的灾难