Exosome educated monocytes for acute radiation syndrome

外泌体训练的单核细胞治疗急性放射综合征

基本信息

批准号：
10458706
负责人：
Christian Capitini
金额：
$ 52.53万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458706
关键词：
Allogeneic Bone Marrow Transplantation Allogenic Anemia Animal Model Biomanufacturing Blood Blood Cells Bone Marrow Bone Marrow Transplantation Bone marrow failure CD34 gene CXCR4 gene Cell Survival Cell Therapy Cells Coculture Techniques Collaborations DNA Development Engineering Exposure to Flow Cytometry Generations Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Histopathology Hour Human Immune Immunodeficient Mouse Individual Infection Infusion procedures Interleukin-6 Label Lead Life Lipopolysaccharides Magnetic Resonance Imaging Mediating Medical Membrane Mesenchymal Stem Cells MicroRNAs Modeling Mus National Security Neonatal Organ Patients Population Pre-Clinical Model Procedures Production RNA Radiation Radiation Dose Unit Radiation Injuries Radiation Protection Radiation Tolerance Radiation Toxicity Radiation exposure Radiation therapy Recovery Risk Role Signal Transduction System TLR4 gene Terrorism Testing Thymus Gland Toxic effect Translations Vesicle Whole-Body Irradiation clinical practice cytokine exosome high risk humanized mouse improved in vivo innovation insight interest macrophage mesenchymal stromal cell mimetics monocyte mortality risk mouse model novel therapeutics radiation effect stem cell exosomes stem cell proliferation success therapy development trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT Finding novel therapies for treatment of radiation-induced toxicities is of value to not only patients who are receiving radiotherapy for different conditions, but also to national security due to risk of terrorism attacks. There is urgent need to develop therapies than can be administered quickly after exposure to minimize the effects of radiation and enhance immune recovery. Preclinical models have informed a great deal of our current clinical practice in managing acute radiation syndrome (ARS). These models can be used to test and develop new cellular therapies. Choosing the proper cell subset, engineering it to produce the necessary cytokines, and understanding how the cells interact with other hematopoietic and immune cells in vivo after infusion are all critical factors in developing a proper cell-based therapy for ARS. Our group has previously characterized an alternatively activated, high IL-6 producing human macrophage subset called mesenchymal stem cell (MSC)-educated macrophages that can enhance survival from lethal ARS using a xenogeneic mouse model as compared to infusions of MSCs or macrophages alone. We have simplified generation of these cells by using exosomes from lipopolysaccharide-stimulated MSCs to educate monocytes into a radioprotective cell subset. The long-term objectives of this proposal are to use MSC-exosomes to improve the generation and efficacy of radioprotective cells and define their mechanism of radioprotection in preclinical models of ARS. We will test the hypotheses that: (1) LPS-high exosome-educated monocytes (LPS-high EEMos) can mediate radioprotection as an allogeneic cell therapy through production of IL-6; (2) LPS-high EEMos protect the host from ARS by trafficking to radiosensitive organs, like bone marrow, and can be tracked by magnetic resonance imaging (MRI); and (3) LPS-mimetics can be used to stimulate MSC exosome production that generate EEMos through let-7b microRNA secretion. Success of any of the individual aims will be a major advance in understanding how monocytes impact blood cell development after ARS. Translation of the entire proposal will lead to an innovative, mechanistic understanding of a new cellular therapy for treating ARS.

项目概要/摘要寻找治疗辐射引起的毒性的新疗法不仅对以下患者有价值：因不同情况接受放射治疗，而且还因恐怖主义袭击的风险而影响国家安全。迫切需要开发能够在暴露后迅速施用的疗法，以尽量减少辐射的影响和增强免疫恢复。临床前模型为我们提供了大量信息当前治疗急性放射综合征（ARS）的临床实践。这些模型可用于测试和开发新的细胞疗法。选择合适的细胞子集，对其进行改造以产生必要的细胞因子，并了解细胞在体内如何与其他造血细胞和免疫细胞相互作用输注都是开发适当的 ARS 细胞疗法的关键因素。我们组此前曾表征了一种交替激活的、高 IL-6 产生的人类巨噬细胞亚群，称为间充质干细胞 (MSC) 培养的巨噬细胞可以使用异种小鼠提高致命 ARS 的存活率模型与单独输注 MSC 或巨噬细胞相比。我们简化了这些细胞的生成使用来自脂多糖刺激的 MSC 的外泌体将单核细胞培养成辐射防护细胞子集。该提案的长期目标是利用 MSC-外泌体来改善生成和放射防护细胞的功效并定义其在 ARS 临床前模型中的放射防护机制。我们将测试以下假设：（1）LPS-高外泌体教育的单核细胞（LPS-高EEMos）可以介导通过产生 IL-6 作为同种异体细胞疗法的辐射防护； (2) LPS高EEMo保护主机通过贩运到骨髓等放射敏感器官来从 ARS 中去除，并且可以通过磁共振进行追踪成像（MRI）； (3) LPS模拟物可用于刺激MSC外泌体的产生，从而产生EEMos 通过let-7b microRNA分泌。任何一个单独目标的成功都将是一个重大进步了解 ARS 后单核细胞如何影响血细胞发育。整个提案的翻译将导致对治疗 ARS 的新细胞疗法的创新、机制理解。