Using human skin grafted mice to identify biomarkers of exposure and study effects of radiation on skin

使用人类皮肤移植小鼠来识别暴露的生物标志物并研究辐射对皮肤的影响

• 批准号: 10112825
• 负责人: Rachael Ann Clark
• 金额: $ 53.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112825
• 关键词: Adult; Age; Antigen-Presenting Cells; Biological; Biological Markers; Childhood; Cutaneous; DNA Repair; Detection; Epithelial; Event; Exposure to; External Beam Radiation Therapy; Gene Expression; Genetic; Goals; Hour; Human; Immune system; Immunocompromised Host; Immunodeficient Mouse; Immunologics; Individual; Institutes; Intervention; Measures; Medical; Modality; Modeling; Morphology; Mus; Neonatal; Nuclear Accidents; Phase; Phenotype; Population; Population Heterogeneity; Proteins; Proxy; Radiation; Radiation Accidents; Radiation Tolerance; Radiation exposure; Rapid screening; Reactive Oxygen Species; Risk; Sampling; Site; Skin; Skin graft; T-Lymphocyte; Testing; Tissues; Validation; base; biomarker discovery; biomarker identification; cohort; innovation; irradiation; medical attention; mouse model; neonatal human; penis foreskin; point of care testing; predictive marker; radiation detector; radiation effect; radiation risk; radiation-induced injury; radiation-induced tissue damage; stem cell population; tissue injury; vascular bed

Summary/Abstract In the event of a large scale radiologic or nuclear event, the immediate needs are to discriminate exposed individuals from the worried well and identify individuals at risk for radiation-induced tissue damage. Humans vary in their sensitivity to radiation-induced tissue injury, the factors that control radiation sensitivity are not fully understood, and there are no biomarkers to identify individuals at risk for radiation-induced tissue damage. The skin is an immunologically active barrier tissue that will be impacted by all types of external radiation events. Skin is visually observable, accessible to non-invasive testing and easily sampled, making it amenable to a variety of testing modalities. We propose to irradiate and study living, immunologically intact human skin grafts on immunodeficient NSG mice to identify biomarkers that detect exposure to radiation and predict radiation induced tissue damage. In Aim 1, we will study the effects of irradiation on adult human skin grafts carried by NSG mice. We will study DNA damage repair proteins, reactive oxygen species, epithelial barrier function and gene expression changes in adult human skin grafts exposed to 0, 0.5, 1.0, 2.0 or 5.0 Gy irradiation. We will identify biomarkers that detect radiation exposure within 24 hours of exposure (Phase I), remain detectable longer term and/or correlate with later tissue injury (Phase II) and we will validate these biomarkers in a separate validation cohort of 30 human skin donors (Phase III). In Aim 2, we will study the effects of irradiation on human neonatal foreskin grafts, a tissue that contains antigen presenting cells but lacks T cells, as a model for both pediatric and immunocompromised populations. We will test biomarkers identified in Aim 1 for their ability to detect radiation exposure within 24 hours and to predict tissue injury in neonatal foreskin. If necessary, we will identify new biomarkers for use in pediatric and immunocompromised populations. In Aim 3, we will develop rapid point-of-care tests to detect the biomarkers we identify in Aims 1 and 2. The skin is an accessible tissue that can be studied as a proxy to predict the risk of radiation-induced injury at other tissue sites. By studying immunologically intact skin from a diverse population of human donors, we will identify biomarkers that are useful in i) humans, ii) a diverse, outbred population with differing sensitivities to radiation, and iii) pediatric and immunocompromised populations. Identification of biomarkers that predict subsequent tissue damage in skin will identify radiation sensitive individuals. Our point-of-care tests have the potential to rapidly screen potentially exposed populations and identify individuals who are at risk for tissue damage and will require further medical attention.

摘要/摘要 在发生大规模放射性或核事件时，立即需要区分暴露的人员 并识别出有辐射引起的组织损伤风险的个体。人类 它们对辐射引起的组织损伤的敏感性各不相同，控制辐射敏感性的因素并不完全 理解，并且没有生物标志物来识别处于辐射引起的组织损伤风险的个体。这 皮肤是一种免疫活性屏障组织，会受到所有类型的外部辐射事件的影响。 皮肤可通过肉眼观察，可进行非侵入性测试，且易于取样，因此适合 多种测试方式。我们建议照射和研究活体、免疫完整的人体皮肤移植物 对免疫缺陷 NSG 小鼠进行研究，以确定检测辐射暴露并预测辐射的生物标志物 诱发组织损伤。在目标 1 中，我们将研究辐射对成人皮肤移植物的影响 NSG 小鼠。我们将研究 DNA 损伤修复蛋白、活性氧、上皮屏障功能和 暴露于 0、0.5、1.0、2.0 或 5.0 Gy 辐射的成人皮肤移植物的基因表达变化。我们将 识别在暴露后 24 小时内检测辐射暴露的生物标志物（第一阶段），并保持可检测性 长期和/或与后来的组织损伤（第二阶段）相关，我们将在 由 30 名人类皮肤捐赠者组成的独立验证队列（第三阶段）。在目标 2 中，我们将研究辐射的影响 以人类新生儿包皮移植物（一种含有抗原呈递细胞但缺乏 T 细胞的组织）为模型 适用于儿童和免疫功能低下人群。我们将测试目标 1 中确定的生物标志物 能够在 24 小时内检测辐射暴露并预测新生儿包皮组织损伤。如果 如有必要，我们将确定用于儿科和免疫功能低下人群的新生物标志物。在目标 3 中， 我们将开发快速现场护理测试来检测我们在目标 1 和 2 中确定的生物标志物。皮肤是 可作为预测其他组织辐射诱发损伤风险的替代指标来研究可触及的组织 网站。通过研究来自不同人类捐赠者群体的免疫完整皮肤，我们将确定 可用于 i) 人类，ii) 对辐射具有不同敏感性的多样化、远交群体， iii) 儿童和免疫功能低下人群。识别预测后续的生物标志物 皮肤组织损伤将识别辐射敏感个体。我们的即时检测有潜力 快速筛查潜在暴露人群并识别有组织损伤风险的个体 将需要进一步的医疗护理。