Immune suppression is one of the most common and most serious consequences of whole body radiatior exposure. If radiation-induced immune suppression is to be prevented or alleviated an improved mechanistic understanding of the subtleties of the interaction of radiation with the immune system is needed. This proposal focuses on two important aspects of radiation-induced immune suppression in a murine model. The first is radiation-induced apoptosis of lymphocytes. The second is the deleterious effects of radiation on dendritic cell (DC) function. We recently described this effect of radiation and believe it may be an important mechanism of immune suppression. In contrast to lymphocytes, which die readily by apoptosis, DCs resist radiation cytotoxicity but their functional ability to process antigen and generate immunity is abrogated. The essential thread of the proposal is that defining agents by the signal transduction pathways the activate and their effects on the proteome is essential for rational development of products capable of protection, mitigation, and therapy of radiation-induced immune suppression. In this project lymphocytes and DCs will be targets for high (HTS) screening of chemical libraries, alongside compounds with known or suspected potential, with the aim of identifying compounds that inhibit radiation lymphocyte cytotoxicity and activate protective signaling pathways in DCs, initially for NF-kappaB but later other reporter gene assays. The results of these screens will be compared with those from yeast radiation-induced DMA damage (Project 1) and, based on potency and biological effects, a subset of agents will be chosen for proteomic screening to broaden their molecular profiling, for testing in in vivo bioassays for immune protection and enhancement, and for their ability to modulate radiation damage in multiple normal tissues. Although this project has an immune focus, the effects of agents on radiation-induced damage in multiple tissues will be determined to see if they have broad effectiveness, or do harm. This study will also help elucidate the interrelationships between agents and critical signal transduction pathways influencing DNA repair, cell survival, and carcinogenesis.
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