Stem Cell-Based Therapies for Mitigation of Acute Radiation Syndromes

描述（由申请人提供）：在大规模伤亡情况下意外或有意的辐射暴露构成了严重和持续的威胁。虽然辐射防护剂在辐射暴露前使用时可以取得一定的成功，但在暴露后使用时用途有限。目前的提案为辐射后战略奠定了基础，以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/干细胞移植提供了一种有效的措施，以改善辐射损伤。与BMT不同，两种细胞移植方法之间的关键区别在于内皮或间充质干细胞移植通过加速造血或肠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缓解的细胞和分子机制。本提案的最终目标是利用该实验系统来鉴定介导受照射的胃肠道、造血或皮肤系统再生的干细胞龛（内皮、间充质和巨噬细胞）中的基质细胞所阐述的因子和信号。本CMCR的所有四个项目都以这一前提为主题，并具有以下目标：定义病理生理机制，发现和验证ARS中的分子靶点，确定如何通过全身给予小鼠生长因子来加速干细胞恢复和再生，检查通过TLR活化和/或基于基质细胞的疗法修复ISC生态位是否可以减轻脊椎动物中的ARS（即小鼠和斑马鱼），并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：缓解辐射诱导的胃肠道综合征（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。项目三：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.