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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084127-03
Application #
8053407
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2009-04-15
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$323,065
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Dekker, Simone E; Nikolian, Vahagn C; Sillesen, Martin et al. (2018) Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury. J Neurosci Res 96:711-719
Nikolian, Vahagn C; Dennahy, Isabel S; Higgins, Gerald A et al. (2018) Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury. J Trauma Acute Care Surg 84:459-465
Bruhn, Peter J; Nikolian, Vahagn C; Halaweish, Ihab et al. (2018) Tubastatin A prevents hemorrhage-induced endothelial barrier dysfunction. J Trauma Acute Care Surg 84:386-392
Chang, Panpan; Weykamp, Michael; Dennahy, Isabel S et al. (2018) Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model. J Trauma Acute Care Surg 84:795-801
Liang, Yingjian; Pan, Baihong; Alam, Hasan B et al. (2018) Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia. Eur J Pharmacol 833:432-440
Deng, Qiufang; Zhao, Ting; Pan, Baihong et al. (2018) Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis. Inflammation 41:2101-2109
He, Wei; Zhou, Peter; Chang, Zhigang et al. (2016) Inhibition of peptidylarginine deiminase attenuates inflammation and improves survival in a rat model of hemorrhagic shock. J Surg Res 200:610-8
Chang, Zhigang; Li, Yongqing; He, Wei et al. (2016) Inhibition of histone deacetylase 6 restores intestinal tight junction in hemorrhagic shock. J Trauma Acute Care Surg 81:512-9
Zhao, Ting; Li, Yongqing; Liu, Baoling et al. (2016) Inhibition of histone deacetylase 6 restores innate immune cells in the bone marrow in a lethal septic model. J Trauma Acute Care Surg 80:34-40; discussion 40-1
Zhao, Ting; Pan, Baihong; Alam, Hasan B et al. (2016) Protective effect of Cl-amidine against CLP-induced lethal septic shock in mice. Sci Rep 6:36696

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