Inflammatory molecules in radiation risk assessment: preclinical drug testing

辐射风险评估中的炎症分子：临床前药物测试

• 批准号: 7929560
• 负责人: PAUL OKUNIEFF
• 金额: $ 103.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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/7929560
• 关键词: Address; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Biological Assay; Blood; Breathing; C57BL/6 Mouse; Categories; Clinical; Cutaneous; DNA Damage; Data; Development; Dose; Drug Delivery Systems; Drug Industry; Effectiveness; Evaluation; Event; Family suidae; Goals; Grant; Growth Factor; Human; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Intestines; Label; Lead; Life; Measurement; Measures; Mediating; Modeling; Modification; Molecular Target; Monitor; Mus; Organ; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Physicians; Plasma; Population; Predisposition; Prevention; Preventive; Process; Protein Array; Radiation; Radiation Toxicity; Radioactive; Radiobiology; Reaction; Resolution; Risk; Risk Assessment; Risk Estimate; Risk Management; Safety; Schedule; Sentinel; Skin; Solid; Specimen; Symptoms; Testing; Therapeutic Agents; Time; Tissues; Toxic effect; Transforming Growth Factor beta; animal data; bone; cell killing; clinically relevant; cytokine; drug testing; indexing; irradiation; man; particle; post-market; pre-clinical; programs; reproductive; research clinical testing; response; senescence; soft tissue; success

Hypothesis: While immediate cell killing and reproductive inactivation by irradiation (IR) is caused by DNA damage, the toxicity is greatly modified by a cascade of inflammatory processes. These processes cause replacement of normal parenchyma by a fibrovascular (FV) proliferative tissue. We propose that inflammatory molecules (IM) exist that define the host inflammatory response and can be measured in the blood (host state) and the exposed tissues (local response). We have identified several IM in the IL-1 and TGFbeta pathways. This new paradigm allows for several avenues of mitigation. Four agent classes have shown promise: growth factors, anti-inflammatory, anti-apoptotic, and antioxidant agents. Studies of solid organs at low IR doses (<10 Gy) and long follow-ups (2 yr), with comprehensive evaluation of IM will test the hypothesis. IM patterns provide a molecular target for mitigating therapies, and for evaluating their effectiveness. We have promising preliminary data in mouse and humans for several agents. Aim 1. Determine the patterns of IM associated with early inflammation and late FV. These studies will be performed using protein arrays of plasma and local tissues. Understanding these patterns will aid in estimating risk of populations and individuals, and will allow for testing the effectiveness of drugs targeting the IM pattern. Aim 2. Identify single agent mitigators of inflammatory toxicity following IR. They will be ranked first using a quick, high resolution, cutaneous toxicity model, followed by a life-shortening model with associated IM measurements. Quantitative dose modifying factors will be measured along with apoptotic and FV indices. Some of the more promising agents will progress to testing in Projects 2, 4, 5, and 6. Aim 3. Investigate combined agents for mitigation of soft tissue inflammation and FV. Multiple classes of agents can be beneficial in different tissues and during different phases after IR. In this aim we will investigate the potential beneficial and deleterious interactions that occur between agents. Goal: Our overall goals are: (1) to identify 2 or 3 high value mitigation agents to be used singly or in combination; and (2) to create a multipurpose IM array, which allows susceptibility estimates for IR induced FV and allows for testing the effectiveness of our mitigation agents.

假设：虽然辐射（IR）导致的立即细胞杀伤和生殖失活是由DNA损伤引起的，但毒性会因一系列炎症过程而大大改变。 这些过程导致纤维血管（FV）增生组织取代正常实质。我们提出，炎症分子（IM）的存在，定义宿主的炎症反应，并可以在血液（宿主状态）和暴露的组织（局部反应）进行测量。我们已经在IL-1和TGF β通路中鉴定了几种IM。这一新的模式允许有几种缓解途径。四类药物已显示出前景：生长因子，抗炎，抗凋亡和抗氧化剂。在低IR剂量（<10戈伊）和长期随访（2年）下对实体器官进行研究，并对IM进行综合评价，将检验这一假设。IM模式为缓解治疗和评估其有效性提供了分子靶点。我们在小鼠和人类中有很有希望的初步数据， 几个特工。目标1.确定与早期炎症和晚期FV相关的IM模式。这些研究将使用血浆和局部组织的蛋白质阵列进行。了解这些模式将有助于估计人群和个人的风险，并将允许测试针对IM模式的药物的有效性。目标2.确定IR后炎性毒性的单药缓解剂。使用快速、高分辨率皮肤毒性模型将其排名第一，其次是与IM相关的缩短寿命模型 测量.将沿着细胞凋亡和FV指数测量定量剂量修饰因子。一些更有前途的代理将在项目2，4，5和6中进行测试。 目标3.研究用于减轻软组织炎症和FV的联合药物。多种类型的代理可以在不同的组织和IR后的不同阶段是有益的。在这个目标中，我们将调查代理之间发生的潜在的有益和有害的相互作用。目标：我们的总体目标是：（1）确定单独或组合使用的2或3种高价值缓解剂;（2）创建多用途IM阵列，其允许对IR诱导的FV进行敏感性估计，并允许测试我们的缓解剂的有效性。