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.

抽象的 滥用电离辐射或核设备作为恐怖主义武器已被认为是 美国主要的公共卫生威胁。这些受害者暴露的受害者的最大风险是造血 急性辐射综合征（H-AR），导致威胁生命的并发症，例如感染和 难治性出血。针对HAR的特定疗法以加速造血再生 辐射损伤很少。由于骨髓内皮细胞可以控制血液学恢复 辐射而无需归骨骨髓，内皮细胞可以介导其辐射保护作用 通过阐述造血细胞因子或可溶性因子。细胞的另一种机制 通信是通过分泌细胞外囊泡来传递蛋白质和核材料 （EV）。电动汽车的大小范围从100-250 nm，并且具有具有潜力的核酸和蛋白质范围 调节相邻的细胞。我们假设EC通过电动汽车发挥其再生作用。我们有 表明用同种异体或同种异体电动汽车治疗受辐照的造血干/祖细胞 从遗传上不同的小鼠中导致干细胞池的相当扩张，这表明它们可能是 免疫学耐受性。与用粒细胞集落刺激因子（G-CSF）处理的对照小鼠相比 电动汽车可能至少具有可比性，并且可能优于G-CSF，以延长 致命剂量照射。我们的压倒性目标是展示电动汽车的放射治疗能力。这样做， 我们将开发一种基于蜂窝的疗法，用于H-AR的HAR，并有可能向受害者提供现成的疗法 大规模伤亡灾难的设置。