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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM071360-01A2
Application #
7097609
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2006-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
1
Fiscal Year
2006
Total Cost
$188,220
Indirect Cost
Name
University of California Davis
Department
Surgery
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Lee, Kang-Hoon; Yee, Lisa; Lim, Debora et al. (2015) Temporal and spatial rearrangements of a repetitive element array on C57BL/6J mouse genome. Exp Mol Pathol 98:439-45
Lee, Kang-Hoon; Rah, HyungChul; Green, Tajia et al. (2014) Divergent and dynamic activity of endogenous retroviruses in burn patients and their inflammatory potential. Exp Mol Pathol 96:178-87
Lee, Kang-Hoon; Lim, Debora; Green, Tajia et al. (2013) Injury-elicited stressors alter endogenous retrovirus expression in lymphocytes depending on cell type and source lymphoid organ. BMC Immunol 14:2
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Lee, Kang-Hoon; Kim, Woo-Chan; Shin, Kyung-Seop et al. (2013) Large interrelated clusters of repetitive elements (REs) and RE arrays predominantly represent reference mouse chromosome Y. Chromosome Res 21:15-26
Lee, Kang-Hoon; Chiu, Sophia; Lee, Young-Kwan et al. (2012) Age-dependent and tissue-specific structural changes in the C57BL/6J mouse genome. Exp Mol Pathol 93:167-72
Lee, Kang-Hoon; You, Ri-Na; Greenhalgh, David G et al. (2012) Identification of a group of Mus dunni endogenous virus-like endogenous retroviruses from the C57BL/6J mouse genome: proviral genomes, strain distribution, expression characteristics, and genomic integration profile. Chromosome Res 20:859-74
Kao, Damian; Hsu, Karen; Chiu, Sophia et al. (2012) ERE database: a database of genomic maps and biological properties of endogenous retroviral elements in the C57BL/6J mouse genome. Genomics 100:157-61

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