Mitigating Cutaneous Radiation Injury with CXCR4 Antagonist

描述（由申请方提供）：拟议研究的目标是开发一种有效的药理学策略，以减轻和治疗人类辐射诱导的皮肤损伤。亚致死剂量电离辐射引起的皮肤损伤对恶性疾病的治疗和辐射防护都有重要意义。严重的皮肤损伤会降低LD 50/60，并增加任何辐射暴露剂量下的死亡风险。可用的对策是次优的，特别是对于皮肤损伤的急性和亚急性阶段。该提案基于这样一种假设，即在亚致死剂量辐射后对皮肤的渐进性损伤部分是由于组织干细胞功能降低，不再能替代分化的功能细胞，导致体内平衡丧失。我们建议用内源性骨髓来源的内皮和基质（间充质）干细胞替代辐射灭菌干细胞的损失。具体而言，我们将确定CXCR 4拮抗剂普乐沙福与血管内皮生长因子（VEGF）联合使用减轻辐射诱导的皮肤损伤的潜力。普乐沙福和VEGF联合使用的基本原理是从骨髓中动员不同的祖细胞亚群。评价的主要终点将是使用半定量评分系统的功能、C57 BL/6小鼠的皮肤强度和腿部收缩。次要终点将包括组织病理学和促炎细胞因子（TGF-β，TNF-α）。我们最近获得了令人鼓舞的数据，显示当暴露后数天应用普乐沙福（CXCR 4拮抗剂）时，放射性皮肤损伤可显著减轻。我们希望我们提出的药理学方法有可能有效地恢复辐射后的组织稳态。 公共卫生相关性：拟议研究的广泛、长期目标是开发一种有效的缓解辐射引起的正常组织和器官损伤的方法。如果成功的话，我们提出的策略将比现有的方法在临床上更有吸引力;内源性骨髓源性干细胞策略应该提供比同种异体甚至同种异体干细胞治疗更安全的方法。

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop an effective pharmacological strategy to mitigate and treat radiation-induced skin injury in humans. Skin injury following a sub- lethal dose of ionizing radiation has important implications both for the treatment of malignant disease and for radiological protection. Significant injuries to the skin decrease the LD50/60 and amplify the risk for death at any radiation exposure dose. Available countermeasures are suboptimal especially with respect to acute and sub-acute phases of the skin injury. The proposal is based on the hypothesis that progressive damage to the skin after sub-lethal dose of radiation is in part due to reduced functioning of the tissue stem cells that can no longer replace differentiated functional cells, resulting in loss of homeostasis. We propose to replace the loss of radiation-sterilized stem cells with endogenous bone marrow derived endothelial and stromal (mesenchymal) stem cells. Specifically, we will determine the potential of the CXCR4 antagonist, plerixafor with vascular endothelial growth factor (VEGF) to mitigate radiation-induced skin injury. The rationale of the combined use of plerixafor and VEGF is to mobilize differentially subsets of progenitor cells from the bone marrow. Primary endpoints for evaluation will be functional using a semi-quantitative scoring system, skin strength and leg contraction in C57BL/6 mice. Secondary endpoints will include histopathology and pro-inflammatory cytokines (TGF-?, TNF-?). We recently obtained encouraging data showing that radiation skin injury could be significantly reduced by plerixafor, CXCR4 antagonist when the drug was applied days after the exposure. We expect that our proposed pharmacological approach has the potential to effectively restore tissue homeostasis after radiation. PUBLIC HEALTH RELEVANCE: The broad, long-term goal of the proposed research is to develop an effective mitigator for radiation-induced normal tissue and organ damage. If successful, our proposed strategy would be clinically more attractive than the existing approach; the endogenous bone marrow derived stem cells strategy should provide a safer approach than allogeneic and even allogeneic stem cell therapy.