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 在发生大规模放射性或核事件时，立即需要区分暴露的 从担心的井中取出个人，并确定有辐射引起的组织损伤风险的个人。人类 尽管它们对辐射诱导的组织损伤的敏感性不同，但控制辐射敏感性的因素并不完全 目前还没有生物标志物来识别有辐射诱导组织损伤风险的个人。的 皮肤是免疫活性屏障组织，其将受到所有类型的外部辐射事件的影响。 皮肤是视觉上可观察的，可以进行非侵入性测试，并且容易取样，使其适合于 各种测试模式。我们建议照射和研究活的，免疫完整的人类皮肤移植 在免疫缺陷NSG小鼠上，以确定检测辐射暴露和预测辐射的生物标志物 导致组织损伤。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， 暴露于0、0.5、1.0、2.0或5.0戈伊辐射的成人皮肤移植物中的基因表达变化。我们将 确定在暴露后24小时内检测辐射暴露的生物标志物（第一阶段）， 长期和/或与后期组织损伤相关（II期），我们将在一项研究中验证这些生物标志物。 30名人类皮肤供体的单独验证队列（III期）。在目标2中，我们将研究辐射的影响 在人类新生儿包皮移植物上，作为模型， 对于儿童和免疫功能低下的人群。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，并预测新生儿包皮的组织损伤。如果 必要时，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， 我们将开发快速的即时检测，以检测我们在目标1和2中确定的生物标志物。皮肤是一个 可触及的组织，可作为预测其他组织辐射诱导损伤风险的替代物进行研究 网站.通过研究来自不同人群的免疫完整的皮肤，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系繁殖群体， 和iii）儿科和免疫功能低下的人群。鉴定预测后续的生物标志物 皮肤的组织损伤将识别出对辐射敏感的个体。我们的即时检测有可能 快速筛查潜在的暴露人群，并确定有组织损伤风险的个人， 需要进一步的医疗护理