Mitigation of Radiation Induced Immune Dysfunction by PrC-210 Treatment

点击翻译按钮获取中文摘要

Mitigation of Radiation-Induced Immune Dysfunction by PrC-210 Treatment PROJECT SUMMARY Human risk of radiation exposure, possibly catastrophic in proportion, has risen. Whether from intentional or unintentional nuclear events, such events could yield thousands to hundreds of thousands of surviving victims. A recent government report stated, “the ideal medical countermeasures for radiation would be those that can both mitigate and protect from injuries.., such a countermeasure remains a significant unmet medical need.” In our earlier work, we invented and have developed a novel, proprietary, compound, PrC-210, which has demonstrated a profound survival benefit to mice when it was administered once 24 hr after an LD95/30 dose of whole-body radiation to the mice. In its preclinical development, PrC-210 has shown multiple protective effects in multiple organ-protection settings; as a radiation countermeasure, PrC-210 was highly effective whether it was administered a day after or 15 min before a 95% lethal radiation dose. PrC-210 has neither nausea nor hypotension side effects. For this proposed U01 research our group will expand upon, and pharmacologically optimize, systemic delivery of PrC-210 at 24 h post-radiation to maximize animal survival and will explore underlying immune and gastrointestinal protection mechanisms to explain the post-radiation, PrC- 210-conferred, survival benefit. Our proof-of-concept studies showed a 45% survival benefit to mice that received a single systemic PrC-210 dose 24 h following a single LD95 dose of ionizing radiation (P=0.002); the PrC-210- treated mice also showed significantly greater body weights (P=0.012) following irradiation, and visibly improved bone marrow cellularity. In this U01, using two established mouse irradiation models, we will identify the best protocol for administering PrC-210 to post-radiation mice, establish the efficacy of PrC-210 in mitigating radiation-induced damage to both immune tissues and circulating immune cells, and establish the efficacy of PrC-210 in protecting the entire gastrointestinal setting from post-radiation immune infiltration and inflammation- associated GI tissue destruction. A host of scored immune endpoints will be measured in post-radiation mice, with and without PrC-210 protection, so we will have multiple, overlapping endpoints of immune function in post- radiation mice, and then see what impact PrC-210 has in protecting them. The goals of this U01 proposal are to: i) determine the optimum +24 hr PrC-210 administration route and dose that confers the greatest survival benefit against an LD95/30 radiation dose, and ii) determine the full extent to which PrC-210 mitigates radiation damage to immune organs and their blood-borne cells, and to gastrointestinal sites and their function in the post-radiation setting. These studies are proposed as a prelude to next-stage PrC-210 clinical trials.