Inflammatory molecules in radiation risk assessment: preclinical drug testing

假设：虽然辐射导致的即时细胞杀伤和生殖失活(IR)是由DNA损伤引起的，但其毒性被一系列炎症过程极大地改变。 这些过程导致纤维血管(FV)增生性组织取代正常实质。我们认为炎症分子(IM)的存在定义了宿主的炎症反应，可以在血液(宿主状态)和暴露的组织(局部反应)中进行测量。我们已经在IL-1和TGFbeta通路中发现了几个IM。这一新的范式允许几种缓解的途径。四类药物已经显示出希望：生长因子、抗炎、抗细胞凋亡和抗氧化剂。对固体器官在低IR剂量(~lt；10Gy)和长期随访(2年)下的研究，以及对IM的综合评估，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一个分子靶点。我们在老鼠和人类身上有很有希望的初步数据 几个特工。目的1.确定与早期炎症和晚期FV相关的IM的类型。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。目的2.确定IR后炎性毒性的单药缓释剂。他们将使用快速、高分辨率的皮肤毒性模型排名第一，紧随其后的是与IM相关的缩短寿命模型 测量。定量剂量修正因子将与细胞凋亡和FV指数一起被测量。一些更有前途的代理将在项目2、4、5和6中进行测试。 目的3.研究减轻软组织炎症和FV的联合用药。在IR后的不同组织和不同阶段，多类药物可能是有益的。在这个目标中，我们将调查发生在代理人之间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2或3个单独或联合使用的高价值缓解剂；(2)创建一个多用途IM阵列，它可以评估IR诱发的FV的敏感性，并允许测试我们缓解剂的有效性。

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.