Thorough
investigation of dysregulated immune responses to Ebola virus (EBOV)
requires an integrated approach that addresses regulation of gene
transcription by epigenetic and non-epigenetic mechanisms,
posttranscriptional mechanisms of gene regulation and posttranslational
protein modifications. Attempts to investigate the lack of function or
altered function of certain host proteins during EBOV infection by
focusing on only some of these mechanisms would not be productive and
would provide an incomplete picture of gene expression in response to
EBOV infection. As such, this Program Project proposal comprises an
integrated approach that will combine both epigenetic and nonepigenetic transcriptional mechanisms (Project 1, Dr. Alexander Bukreyev,
Project Lead, UTMB), posttranscriptional mechanisms (Project 2, Dr.
Mariano Garcia-Blanco, Project Lead, UTMB) and posttranslational protein
modifications (Project 3, Dr. Ricardo Rajsbaum, Project Lead, UTMB) caused by EBOV infection. All three Research Projects require the BSL-4 Core (Core B, Dr. Alexander Bukreyev,
Core Lead, UTMB), which will be responsible for performing infections
of human immune and non-immune cells, as well as mice and nonhuman
primates, and also
will perform the initial steps of experiments that involve infectious
virus. Analysis of infected immune cells will be performed by the Proteogenomics
Core (Core C, Dr. Andrew Routh, Core Lead, UTMB); the results will be
analyzed using bioinformatics and modeling approaches (Core D, Dr. Ivan
Marazzi, Core Lead, Icahn School of Medicine at Mount Sinai) to
investigate the nature of dysregulated immune response to EBOV. An
Administrative Core (Core A, Dr. Alexander Bukreyev, Core Lead) will function as the critical coordinating component of the P01. The combined
approach that we propose will provide the most detailed view of the
host immune response to EBOV infection yet described.