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: 10551268
• 负责人: Rachael Ann Clark
• 金额: $ 60.92万
• 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/10551268
• 关键词: Adult; Age; Antigen-Presenting Cells; Biological; Biological Markers; Childhood; Cutaneous; DNA Repair; Detection; Epithelium; Event; Exposure to; External Beam Radiation Therapy; Gene Expression; Genetic; Goals; Hour; Human; Immune system; Immunocompromised Host; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunologics; Individual; Intervention; Measures; Medical; Modality; Modeling; Morphology; Mus; Neonatal; Nuclear Accidents; Phase; Phenotype; Population; Population Heterogeneity; Probability; 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; Visual; biomarker discovery; biomarker identification; biomarker validation; 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; risk prediction; 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 如果发生大规模的放射线或核事件，则直接需求是区分暴露 来自担心的个体，并确定有辐射引起的组织损伤风险的个体。人类 它们对辐射诱导的组织损伤的敏感性不同，控制辐射敏感性的因素不是完全 理解，并且没有生物标志物可以识别有辐射引起的组织损伤风险的个体。这 皮肤是一种免疫主动的屏障组织，将受到所有类型的外部辐射事件的影响。 皮肤在视觉上可以观察到，可用于非侵入性测试并易于采样，使其适合于 多种测试方式。我们建议照射和研究生活，免疫学完整的人类皮肤移植物 在免疫缺陷的NSG小鼠上，以识别检测到辐射暴露并预测辐射的生物标志物 诱导组织损伤。在AIM 1中，我们将研究辐射对成人人类皮肤移植的影响 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 成人人类皮肤移植物的基因表达变化，暴露于0、0.5、1.0、2.0或5.0 Gy辐照。我们将 识别在暴露后24小时内检测到辐射暴露的生物标志物（I期）仍可检测到 长期和/或与以后的组织损伤相关（II期），我们将在A中验证这些生物标志物 单独的验证队列30人皮肤供体（第三阶段）。在AIM 2中，我们将研究辐射的影响 在人类新生儿包皮移植物上，一种包含抗原呈现细胞但缺乏T细胞的组织作为模型 针对小儿和免疫功能低下的人群。我们将测试AIM 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中的组织损伤。如果 有必要的是，我们将确定用于小儿和免疫功能低下的人群中的新生物标志物。在AIM 3中， 我们将开发快速的护理测试，以检测目标1和2中我们识别的生物标志物。皮肤是一种 可访问的组织可以作为代理，以预测其他组织辐射诱导的损伤的风险 站点。通过研究来自各种人类捐助者的免疫学完整皮肤，我们将确定 在i）人类中有用的生物标志物，ii）多种多样的人群，对辐射的敏感性不同， iii）小儿和免疫功能低下的人群。识别预测随后的生物标志物 皮肤的组织损伤将识别辐射敏感的个体。我们的护理点测试有可能 迅速筛查潜在暴露的人群，并确定面临组织损伤风险的人 将需要进一步的医疗护理。