Modulation of Acetylation in the Treatment of Lethal Injuries



 DESCRIPTION (provided by applicant): Hemorrhage and brain injuries are the leading causes of death in civilian and military trauma. Current therapies are mostly supportive, and do not address the specific cellular dysfunction caused by shock and injuries. Acetylation is rapidly emerging as a key epigenetic mechanism that regulates the expression of numerous genes (by modulating nuclear histones), as well as the functions of multiple non-nuclear proteins. Funded by the NIH grant R01GM84127, we have demonstrated that treatment with non-selective histone deacetylase (HDAC) inhibitors (pan-HDACI) can rapidly activate key mechanisms that lead to improved survival in animal models of lethal hemorrhage, sepsis, and combined insults. These results have allowed us to start a federally funded phase-I clinical trial of a pan-HDACI, valproic acid (ClinicalTrials.gov identifier NCT01951560). Although exciting, treatment with non-selective HDACI is not optimal due to need for very large doses, which creates a significant potential for toxicities. The 18 known isoforms of HDAC have very distinctive roles, tissue distribution, and physiological functions, and newer inhibitors are more isoform selective, and thus more disease specific. We have recently shown that treatment with isoform specific HDACI (iso-HDACI) is more effective than pan-HDACI in septic models, and preliminary data suggest that this may also be true for other lethal insults. However, this area needs additional investigation because appropriate selection of the drug(s) is critically important, and inhibition f the wrong HDAC can be detrimental. The proposed research is a logical extension of our previous work, and combines in-vivo experiments with cellular and molecular assays to identify novel treatments for lethal insults, and to provide important insights into the underlying mechanisms. Long-term goal: Develop novel strategies to minimize cellular damage and improve survival after lethal insults. Specific aim 1: Test the effectiveness of iso-HDACIs when given after uncomplicated lethal blood loss (without poly-trauma) in a rodent model. Specific aim 2: Determine whether addition of iso-HDACI to resuscitation regimens would improve outcomes in clinically realistic models, where hemorrhagic shock is complicated by multiple organ injuries and polymicrobial contamination. Specific aim 3: Determine the dominant mechanisms that are responsible for the multi-organ protective effects of the iso-HDACI following diverse insults, in two different species. Approach: Our plan is to perform a series of animal experiments to address the 3 specific aims. First, a rodent model of uncomplicated blood loss will be used to compare the iso-HDACI to pan-HDACI, and to understand the interplay between various iso-HDACIs and other cytoprotective strategies. The strategies that work well in this model will then be further validated in a clinically realistic swine model of hemorrhage, poly-trauma, and [polymicrobial contamination (colon injury)]. Tissues from these experiments will be used to elucidate the underlying mechanisms at the level of genes, proteins, metabolism, and important cellular functions.