Endogenous retroviruses and gene regulation after injury

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DESCRIPTION (provided by applicant): We have identified changes (activation or repression) in the expression of murine endogenous retroviruses (MuERVs) in distant organs of C57BL/6J mice after burn. A role for endogenous retroviruses (ERVs) in inflammation and disease is exemplified by the recent finding that syncytin, an envelope protein encoded by a human endogenous retrovirus, is directly involved in the pathologic processes of multiple sclerosis. It is our hypothesis that burn-mediated alterations in activities of certain ERVs contribute to the systemic response, particularly the immune disorder after burn. These ERVs exert pathologic effects via their retroviral activities and gene products as well as altering expression of neighboring cellular genes near their integration sites. In aim 1, we will establish a chromosomal map of MuERVs in the genome of C57BL/6J mice. This aim will perform in silico chromosomal mapping of MuERVs, evaluation of their coding potentials for retroviral polypeptides, and identification of cellular genes neighboring individual proviral loci. Aim 2 will focus on determination of the transcriptional potential of each group of MuERVs sharing the same U3 promoter sequence in vitro. Because the key transcriptional regulatory elements responsible for the expression of MuERVs reside mainly on the highly polymorphic U3 promoter sequences, transcriptional activities from each group of U3 promoters will be determined by luciferase reporter assay and transcription regulatory element analysis. In aim 3, the pathophysiologic roles of MuERVs whose expression is modulated in response to burn/stress signals in the post-burn immune disorder will be analyzed. Initially, to identify MuERVs which may play a role in the post-burn immune disorder, alterations in retroviral expression in distant organs as well as the systemic circulation will be examined. Recombinant MuERVs that carry specific U3 sequences whose transcriptional activities are altered in response to burn and/or stress signals will be constructed and the role of these MuERVs in the post-burn immune disorder will be investigated in vitro cell culture as well as in vivo infection model. The data from these studies may elucidate an alternative direction for the development of a novel therapeutic regimen (e.g., retroviral reverse transcriptase inhibitor, protease inhibitor) in regard to the modulation of endogenous retroviral activities under the conditions of burn, trauma, bacterial infection, and other types of stresses.