Excellence in Research: Stress-induced expression and release of DAMPs: Regulatory role of Epigenetic Factors and Post-translational modifications

Southern University, Baton Rouge LA

Investigators

Abstract

An idea that has gained support in recent years is that epigenetic changes to DNA and natural cellular modifications to proteins may effect stress-induced immune responses. One of the major consequences of cellular stress is the production and secretion of Danger-Associated Molecular Patterns (DAMPS). The DAMPs, including high-mobility group box protein 1 (HMGB1) and heat-shock protein 70 (HSP70), induce inflammation in mammals by interacting with pattern-recognition receptor proteins (proteins capable of recognizing DAMP molecules). Earlier studies provide evidence about the possible role of chemical modifications to proteins in the secretion of HMGB1 by stressed cells. We do not know, however, if these modifications also affect secretion of HSP70. In this project, the investigators will use both computational and cell biological approaches to measure chemical changes to both DNA and proteins responsible for the release of DAMPs from lung and liver cells challenged with pentachlorophenol, a widely used organochlorine herbicide and wood preservative. The incorporation of computational approaches to understand these basic cellular mechanisms will greatly improve the research approach employed at the participating HBCU Campuses, Southern University in Baton Rouge and Grambling State University, both in Louisiana. An important highlight of this project is to increase the number of undergraduate African-American students entering careers as research scientists by providing these HBCU students with faculty-supervised training from qualified and trained HBCU Ph.D. students, which will also develop the mentoring abilities of the latter. This Excellence in Research award will enable the investigators to develop and establish a rigorous and high-quality research program that will significantly improve the research experience and education of minority students in Louisiana. The proposal investigates the molecular mechanisms associated with the endogenous expression and extracellular release of Danger-Associated Molecular Patterns (DAMPs) in cellular models under stressed conditions. The DAMPs include high-mobility group box protein 1 (HMGB1) and heat-shock protein 70 (HSP70). These proteins induce inflammation through interaction with cell surface or cytosolic pattern recognition receptors. Earlier studies provided evidence about the possible role of post-translational modification (PTM) in the secretion of HMGB1 by stressed cells, but little is known about HSP70’s secretory mechanisms. The investigators on this project will use both computational and cell biological approaches to identify the epigenetic factors and PTMs responsible for the release of DAMPs from lung and liver cells challenged with pentachlorophenol, an organochlorine herbicide and wood preservative. This will be accomplished in part through measurement of epigenetic methylation of DNA on CpG sequences in promoter regions of genes encoding DAMPs, as well as measurements of histone modifications in those same promoter regions. The additional incorporation of computational approaches to understand the basic cellular mechanisms will transform the research approaches being employed at the two participating HBCU Campuses, Southern University in Baton Rouge and Grambling State University, both in Louisiana. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.