Inflammatory molecules in radiation risk assessment: preclinical drug testing

假设：虽然辐射（IR）的直接细胞杀伤和生殖失活是由DNA损伤引起的，但毒性被一系列炎症过程大大改变。

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.