Hemorrhage is the leading cause of death in civilian and combat trauma, and effective resuscitation strategies have the potential of saving many lives. However, conventional resuscitation can exacerbate cellular injury caused by hemorrhagic shock. At a sub-cellular level, hemorrhagic shock and resuscitation can alter gene expression, and impair the regulation of subsequent downstream survival pathways. Nuclear histone proteins are known regulators of gene transcription, and we have previously shown that treatment with histone deacetylase inhibitors (HDACI) enhances gene transcription through specific hyperacetylation at multiple lysine residues ("epigenetic regulation"), attenuates organ damage, and improves early survival after lethal hemorrhage. Emerging evidence also suggests that acetylation of non-histone proteins may play an equally important regulatory role in cellular processes, independent of transcription. Thus, administration of HDACI (with or without conventional fluid resuscitation) appears to be a very promising strategy for the treatment of lethal hemorrhage. However, before these exciting findings can be translated into clinical practice, the most effective HDACI treatment (e.g. agent, dose, and timing), and the precise mechanisms of action must be clearly identified. LONG TERM GOALS: Develop strategies to minimize cellular injury and improve survival after lethal hemorrhage.
SPECIFIC AIM 1 : Identify the histone deacetylase inhibitor (HDACI) treatment that induces the most pronounced acetylation, when given after lethal non-resuscitated hemorrhage? Sub aim 1: Identify the optimal doses of HDACI for achieving maximum protein acetylation.
Sub aim 2 : Determine whether protein hyperacetylation can be sustained for longer duration through repeated administration of HDACI.
Sub aim 3 : Determine whether combining agents from different HDACI groups can enhance protein acetylation.
SPECIFIC AIM 2 : Establish whether addition of HDACI to resuscitation fluids is advantageous? Sub aim 1: Ascertain whether addition of HDACI to conventional fluids attenuates markers of cellular injury and improves survival? Sub aim 2: Determine whether HDACI treatment can be combined with hypertonic fluid resuscitation to achieve synergistic effects? SPECIFIC AIM 3: Determine the dominant mechanisms that are responsible for exerting the protective effects of HDACI.
Sub aim 1 : Identify the genes whose transcription is altered by the acetylation of histone proteins ("epigenetic mechanisms"), and study its impact on downstream proteins.
Sub aim 2 : Identify whether the protective effects of HDACI are due to direct acetylation of non-histone proteins.
Conventional methods of treating massive blood loss have proven to be ineffective, and may even worsen the outcome. Our research has shown that survival can be dramatically improved by enhancing the essential protective mechanisms that are naturally present in the cells.
The aim of our project is to refine this novel approach, and develop effective strategies for the treatment of lethal blood loss.
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