Protein biomarker dosimetry

蛋白质生物标志物剂量测定

• 批准号: 7676111
• 负责人: AMANDA G PAULOVICH
• 金额: $ 62.34万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7676111
• 关键词: Acute; Animal Model; Antibodies; Appearance; Biological Assay; Biological Markers; Blood; Blood specimen; Bone Marrow Transplantation; Canis familiaris; Cells; Cellular biology; Chronic; Clinical; Condition; Count; Data; Dependence; Detection; Development; Diagnostic; Dicentric chromosome; Disasters; Dose; Dose-Rate; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Goals; Hematopoiesis; Hour; Human; Individual; Intervention; Ionizing radiation; Kinetics; Life; Lymphocyte Depletion; Measures; Medical; Modeling; Monitor; Patients; Performance; Peripheral Blood Mononuclear Cell; Phospho-Specific Antibodies; Plasma; Pregnancy Tests; Proteins; Proteome; Proteomics; Radiation; Radiation Tolerance; Range; Reagent; Reference Values; Resources; Screening procedure; Series; Stem cell transplant; Supportive care; Techniques; Technology; Testing; Time; Toxic effect; Treatment Protocols; Triage; Urine; Variant; Vomiting; Whole-Body Irradiation; base; biodosimetry; cancer risk; clinically relevant; cohort; day; dosimetry; exposed human population; improved; in vivo; innovation; response

Moderate exposure to ionizing radiation can be survived with appropriate clinical intervention, which ranges from supportive care to stem cell transplant, depending on dose of exposure. Therefore, rapid triage of exposure victims based on biodosimetry is essential for saving lives and optimizing deployment of resources during a disaster. Current biodosimetry based on parameters such as time to onset of vomiting, lymphocyte depletion kinetics, and the appearance of dicentric chromosomes are less than ideal because they require at least 2-3 days for analysis and they are not easily automated. The goal of this project is to develop a sensitive and automated dosimetric assay. This proposal is significant because development of rapid and automated assays for quantifying exposure would greatly improve triage and thereby improve survival of victims. Our approach is to develop protein-based diagnostics that can be deployed "in the field" without sophisticated technology to assess exposure immediately. Human cells exhibit a robust, radiation-induced proteomic response detectable within minutes following exposure, and many of these proteomic changes show highly reproducible dose- and time-dependence and hence hold great promise for biodosimetry. The objective of this proposal is to test the hypothesis that changes in the human proteome (plasma, urine, or peripheral blood mononuclear cells) in response to radiation can serve as clinical biomarkers to determine radiation exposure levels. This approach is innovative, since there are currently no protein diagnostics for radiation exposure. As an end product to this study, we envision development of blood- or urine-based protein diagnostics, similar to the widely available, over-the-counter pregnancy test. However, rather than monitoring pHCG, our tests would monitor proteins responding to radiation. Specific aim 1: Develop ELISA assays and reagents for quantifying radiation-induced proteomic changes. Specific aim 2: Determine the biodosimetry of radiation-induced protein biomarkers ex vivo (PBMCs) and in vivo in a dog model. Specific aim 3: Determine the biodosimetry of radiation-induced protein biomarkers ex vivo (PBMCs) and in vivo in humans.

通过适当的临床干预措施，可以通过适当的临床干预措施幸存下来，从支撑性护理到干细胞移植，具体取决于暴露剂量。因此，基于生物措施的快速分类对挽救生命和优化灾难中资源部署至关重要。当前基于参数的生物测量法，例如呕吐的时间，淋巴细胞耗尽动力学以及二乙烯染色体的外观不理想，因为它们至少需要2-3天进行分析，并且它们不易自动化。该项目的目的是开发一种敏感且自动化的剂量法测定法。该提议很重要，因为快速发展和 量化暴露的自动测定方法将大大改善分类，从而改善受害者的生存。我们的方法是开发基于蛋白质的诊断方法，这些诊断可以在没有精致技术的情况下“在现场”部署，以立即评估暴露。人类细胞在暴露后几分钟内表现出强大的，辐射诱导的蛋白质组学反应，其中许多蛋白质组学变化表现出高度可重现的剂量和时间依赖性，因此对生物测量法具有很大的希望。该提案的目的是检验以下假设：响应辐射的人类蛋白质组（血浆，尿液或外周血单核细胞）的变化可以作为临床生物标志物来确定 辐射暴露水平。这种方法是创新的，因为目前没有用于辐射暴露的蛋白质诊断。作为这项研究的最终产品，我们设想开发基于血液或尿液的蛋白质诊断，类似于广泛可用的非处方妊娠试验。但是，我们的测试不是监测PHCG，而是监测对辐射响应的蛋白质。特定目的1：开发ELISA分析和试剂，以量化辐射诱导的蛋白质组学变化。具体目标2：确定辐射诱导的蛋白质生物标志物的生物测定法（PBMC）和狗模型中的体内。特定目标3：确定辐射诱导的蛋白质生物标志物的生物测量法（PBMC）和IN 人类的体内。