Discovering tissue-specific biomarkers of radiation injury in SILAC-labeled mice

在 SILAC 标记的小鼠中发现辐射损伤的组织特异性生物标志物

• 批准号: 8484349
• 负责人: AMANDA G PAULOVICH
• 金额: $ 44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-06 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484349
• 关键词: Accidents; Acute; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood Tests; Bone Marrow; Cause of Death; Cessation of life; Childhood; Clinical; Creatine Kinase; Development; Devices; Diagnosis; Diagnostic; Dose; Dose-Rate; Effectiveness; Elderly; Emergency Care; Emergency Situation; Ensure; Environmental Risk Factor; Extravasation; Gender; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hospitals; Hour; Human; Immunoassay; Individual; Injury; Institution; Label; Lipase; Marrow; Measures; Medical; Methods; Modality; Mus; Muscle; Myocardial Infarction; Nuclear; Organ; Pancreas; Panic; Patients; Plasma; Population Heterogeneity; Process; Proteins; Proteomics; Radiation; Radiation Injuries; Radiation Sicknesses; Recording of previous events; Residual state; Risk; Severities; Signal Transduction; Signs and Symptoms; Specificity; Stem cell transplant; Supportive care; Syndrome; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Transaminases; Triage; Troponin; Validation; base; care systems; cytokine therapy; injured; innovation; irradiation; liver injury; novel; point of care; prevent; response; success; urban area

DESCRIPTION (provided by applicant): At total body radiation exposures of 3-8 Gy, the predominant cause of death is the hematopoietic syndrome. Many of these deaths are preventable with rapid triage of victims for cytokine therapies and aggressive supportive care. Unfortunately current modalities for identifying patients at risk for the hematopoietic syndrome suffer from inaccuracy, high expense, long analysis times, and delayed diagnosis. Furthermore, none of these methods directly measures radiation damage to the bone marrow, nor do they indicate the existence of residual hematopoiesis, and most are not amenable to point-of-care in emergency conditions. Thus, there is a critical unmet need for a field-deployable diagnostic for use following a radiological incident to identify victims who will develop the potentially fatal ye often treatable hematopoietic syndrome. We propose to build upon a highly successful paradigm in clinical diagnostics, which is that injured tissues leak, shed, and/or secrete proteins into the plasma, where they are useful biomarkers indicating the extent of tissue injury. Precedents include the troponins in myocardial infarction, transaminases in liver injury, creatine kinase in muscle injury, and lipase in pancreatic processes. Accordingly, we hypothesize that following radiation-induced injury to the bone marrow, proteins are released from the marrow into the bloodstream, where they provide useful biomarker signals predictive of the onset and severity of the hematopoietic syndrome. We propose to identify these plasma biomarkers of radiation-induced marrow injury using an innovative approach incorporating targeted proteomic technologies that we have developed and validated in a biomarker discovery pipeline that will substantially increase our chances of success compared with traditional approaches by enabling the testing of a very large (unprecedented) number of plasma biomarker candidates. Aim 1. Using SILAC-labeled mice, identify proteins induced in the bone marrow in response to radiation, and subsequently test hundreds of these putative tissue injury markers to identify the subset that are stably elevated in the plasma post-exposure. Aim 2: Characterize candidate marrow injury biomarkers identified in Aim 1 with respect to their: a. stability in plasma over time, dose range, and dose rates b. correlation with clinical endpoints (indicators of hematopoietic syndrome) c. specificity for damage to the hematopoietic system and damage caused by radiation d. use across a heterogeneous population (pediatric, geriatric, gender, genetically susceptible) Aim 3. Determine which of the radiation biomarkers of marrow damage identified in the mouse are elevated in human blood following radiation exposure, and develop a point-of-care assay device that will form the basis of subsequent human clinical validation trials (beyond this proposal).

描述（由申请人提供）：在3-8 Gy的全身总辐射照射下，主要死亡原因是造血综合征。通过对受害者进行快速分诊，接受细胞因子治疗和积极的支持性护理，其中许多死亡是可以预防的。不幸的是，目前用于识别造血综合征高危患者的方法存在不准确、费用高、分析时间长和诊断延迟等问题。此外，这些方法都不能直接测量对骨髓的辐射损伤，也不能表明是否存在残留的造血功能，而且大多数方法在紧急情况下不适合在护理点使用。因此，急需一种可在现场部署的诊断方法，以便在放射事故后使用，以确定可能患上致命但通常可治疗的造血综合征的受害者。我们建议在临床诊断中建立一个非常成功的范例，即受伤组织泄漏，脱落和/或分泌蛋白质