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.
| Zhang, Steven B; Yang, Shanmin; Zhang, Zhenhuan et al. (2017) Thoracic gamma irradiation-induced obesity in C57BL/6 female mice. Int J Radiat Biol 93:1334-1342 |
| Groves, Angela M; Johnston, Carl J; Misra, Ravi S et al. (2015) Whole-Lung Irradiation Results in Pulmonary Macrophage Alterations that are Subpopulation and Strain Specific. Radiat Res 184:639-49 |
| Zhang, Steven B; Yang, Shanmin; Vidyasagar, Sadasivan et al. (2015) PicoGreen assay of circular DNA for radiation biodosimetry. Radiat Res 183:188-95 |
| Yang, Shanmin; Zhang, Mei; Chen, Chun et al. (2015) Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis. Radiat Res 184:509-17 |
| Yin, Liangjie; Vijaygopal, Pooja; Menon, Rejeesh et al. (2014) An amino acid mixture mitigates radiation-induced gastrointestinal toxicity. Health Phys 106:734-44 |
| Johnston, Carl J; Manning, Casey M; Rangel-Moreno, Javier et al. (2013) Neonatal irradiation sensitizes mice to delayed pulmonary challenge. Radiat Res 179:475-84 |
| Xiao, Zhenyu; Yang, Shanmin; Su, Ying et al. (2013) Alteration of the inflammatory molecule network after irradiation of soft tissue. Adv Exp Med Biol 765:335-341 |
| Chen, Chun; Yang, Shanmin; Zhang, Mei et al. (2013) In vitro Sirius Red collagen assay measures the pattern shift from soluble to deposited collagen. Adv Exp Med Biol 765:47-53 |
| Cherry, Jonathan D; Williams, Jacqueline P; O'Banion, M Kerry et al. (2013) Thermal injury lowers the threshold for radiation-induced neuroinflammation and cognitive dysfunction. Radiat Res 180:398-406 |
| Ma, Jun; Hou, Yanqian; Han, Deping et al. (2013) Fibroblast growth factor-peptide promotes bone marrow recovery after irradiation. Adv Exp Med Biol 765:155-161 |
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