Stem Cell-Based Therapies for Mitigation of Acute Radiation Syndromes

描述（由申请人提供）：在大规模伤亡环境中意外或预期的辐射暴露呈现出严重和持续的威胁。虽然在辐射照射前使用放射防护剂可以取得一些成功，但在照射后使用时作用有限。目前的提案为辐射后战略奠定了基础，以便在辐射事件发生后几天内保护受ARS影响的关键组织。这种方法是基于强有力的初步证据，基质/干细胞移植是改善辐射损伤的有效措施。与骨髓移植不同，两种细胞移植方法的关键区别在于内皮细胞或间充质干细胞移植通过加速造血或肠道再生或伤口愈合介导受损宿主干细胞的恢复，而不是用供体来源的细胞替代。这提供了一种新的方法来确定负责辐射减缓的细胞和分子机制。本研究的最终目标是利用该实验系统来确定干细胞生态位（内皮细胞、间充质细胞和巨噬细胞）中基质细胞介导辐照后胃肠道、造血或皮肤系统再生的因素和信号。本次CMCR的四个项目在主题上都是基于这一前提，并有以下目标：明确ARS的病理生理机制，发现和验证分子靶点，确定如何通过全身给药小鼠生长因子加速干细胞的恢复和再生，研究通过TLR激活和/或基质细胞治疗修复ISC生态位是否可以减轻脊椎动物（即小鼠和斑马鱼）的ARS，探索信号转导调节剂替代和放大干细胞存活和再生所需信号的潜力。项目1：缓解辐射诱发的胃肠道综合征（RIGS）的干细胞疗法。项目2：内皮细胞衍生因子缓解骨髓综合征。项目3：基于纳米颗粒的皮肤辐射综合征治疗和项目4：通过调节炎症信号通路减轻辐射损伤。

DESCRIPTION (provided by applicant): Accidental or intended radiation exposure in a mass casualty setting presents a serious and ongoing threat. While radioprotective agents can be used with some success when given prior to radiation exposure they are of limited use when used post-exposure. The current proposal prepares the groundwork for a post radiation strategy to protect critical tissues affected by ARS within days after the radiation event has occurred. This approach is based on strong preliminary evidence that stromal/stem cell transplantation provides an effective measure to ameliorate radiation injury. Unlike BMT, the critical difference between the two cell transplantation approaches is that endothelial or mesenchymal stem cell transplantation mediates the recovery of damaged host stem cells via accelerated hematopoiesis or intestinal regeneration or wound healing rather than its replacement with donor derived cells. This provides a novel approach to identify the cellular and molecular mechanisms responsible for radiation mitigation. The ultimate goal of this proposal is to exploit this experimental system to identify the factors and signals elaborated by the stromal cells in the stem cell niche (endothelial, mesenchymal and macrophages) that mediate the regeneration of the irradiated gastrointestinal, hematopoietic or cutaneous system. All four projects of this CMCR are thematically based on this premise and have the following objectives: Define pathophysiologic mechanisms, discovery and validation of molecular targets in ARS , Determine how to accelerate stem cell recovery and regeneration by systemic administration of growth factors in mice, Examine whether repair of the ISC niche by TLR activation and/or stromal cell-based therapies could mitigate ARS in vertebrates (i.e. mice and zebrafish), and Explore the potential of modulators of signal transduction to substitute and amplify signals necessary for stem cell survival and regeneration. Project 1: Stem cell-based therapies for mitigation of radiation-induced gastrointestinal syndrome (RIGS). Project 2: Endothelial cell-derived factors for mitigation of bone marrow syndrome. Project 3: Nanoparticle-based therapies for cutaneous radiation syndrome and Project 4: Mitigation of radiation damage by modulating inflammatory signaling pathways.