Isoform Specific Histone Deacetylase Inhibitor Treatment in a Swine Model of Polytrauma and Sepsis

异构体特异性组蛋白脱乙酰酶抑制剂治疗多发伤和脓毒症猪模型

基本信息

批准号：
9794007
负责人：
Ben Edwin Biesterveld
金额：
$ 6.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794007
关键词：
Acetylation Adverse effects Adverse reactions Affect Aftercare American Americas Animal Model Brain Cause of Death Cell Culture Techniques Cell Death Cell Line Cell Survival Cessation of life Clinical Cognitive Colon Crush Injury Data Dose Effectiveness FDA approved Family suidae Functional disorder Genes Genomics Grant Hemorrhage Hemorrhagic Shock Histology Histone Deacetylase Histone Deacetylase Inhibitor Injury Intra-abdominal Laceration Lesion Liver Magnetic Resonance Imaging Measures Military Personnel Modeling Neurological outcome Outcome Pathway interactions Patients Phenotype Physiological Protein Isoforms Proteins Proteomics Resuscitation Rib Fractures Rodent Model Sepsis Septic Shock Shock Testing Therapeutic Effect Tissues Toxic effect Trauma Traumatic Brain Injury Traumatic injury United States National Institutes of Health Work blood product cognitive function cognitive testing improved inhibitor/antagonist mortality novel novel therapeutics prevent soft tissue targeted treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Traumatic injuries are the leading cause of death in young Americans. In civilian and military trauma, hemorrhage and traumatic brain injuries (TBI) account for the majority of these deaths. Current treatment is focused on hemorrhage control, blood product resuscitation and support of physiologic parameters. No therapy exists to specifically prevent cellular dysfunction that occurs with shock or traumatic injuries. We have shown that in clinically realistic models of trauma, hemorrhagic shock and TBI, treatment with nonselective histone deacetylase (HDAC) inhibitors improves survival and cognitive function. However, the doses needed for this effect have been very high, raising concern for toxicity. There are 18 known isoforms of HDAC, and we believe that being able to develop a more targeted therapy to inhibit specific isoforms of HDAC would achieve the desired therapeutic effect while decreasing concern for toxicity and adverse reactions. This proposal is a continuation of work done on NIH grant R01GM84127. As part of this grant, we have tested various isoform specific HDAC inhibitors in cell line and rodent models of hemorrhage, trauma and septic shock. Work from cell culture data and small animal models will be used to select the appropriate isoform specific HDAC inhibitors to test in a clinically realistic swine model of hemorrhagic shock, polytrauma including TBI and intra- abdominal sepsis. Using this model, we will be able to compare long term survival and cognitive outcomes after treatment with conventional resuscitation, nonselective HDAC inhibitor and isoform specific HDAC inhibition. Additionally, tissue from swine will be used to elucidate underlying mechanisms that contribute to cell death and dysfunction during trauma, and how HDAC inhibition promotes a “pro-survival” phenotype at the genomic and proteomic level.

项目概要/摘要外伤是美国年轻平民和军人死亡的主要原因。外伤、出血和创伤性脑损伤（TBI）占这些死亡的大部分。目前的治疗重点是控制出血、血液制品复苏和支持不存在专门预防细胞功能障碍发生的治疗方法。我们已经证明，在临床真实的创伤模型中，失血性休克和 TBI，使用非选择性组蛋白脱乙酰酶 (HDAC) 抑制剂治疗提高生存率和认知功能。然而，这种效果所需的剂量是有限的。非常高，引起人们对毒性的担忧。我们相信 HDAC 有 18 种已知亚型。能够开发出更有针对性的疗法来抑制 HDAC 的特定亚型将达到预期的治疗效果，同时减少对毒性和不良反应的担忧该提案是 NIH 拨款 R01GM84127 工作的延续。这笔资助，我们在细胞系和啮齿动物中测试了各种异构体特异性 HDAC 抑制剂根据细胞培养数据和小动物建立出血、创伤和感染性休克模型。模型将用于选择合适的异构体特异性 HDAC 抑制剂来进行测试失血性休克、多发伤（包括 TBI 和体内损伤）的临床真实猪模型使用该模型，我们将能够比较长期生存率和认知能力。常规复苏、非选择性 HDAC 抑制剂和治疗后的结果此外，猪的组织将用于阐明异构体特异性 HDAC 抑制。创伤期间导致细胞死亡和功能障碍的潜在机制，以及如何 HDAC 抑制可在基因组和蛋白质组水平上促进“促生存”表型。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Validation of intraosseous delivery of valproic acid in a swine model of polytrauma.

DOI：
10.1136/tsaco-2021-000683
发表时间：
2021
期刊：
Trauma surgery & acute care open
影响因子：
2
作者：
Biesterveld BE;O'Connell R;Kemp MT;Wakam GK;Williams AM;Pai MP;Alam HB
通讯作者：
Alam HB

Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

在长期损害控制复苏的猪模型中，丙戊酸可提高存活率并降低复苏要求。

DOI：
10.1097/ta.0000000000002281
发表时间：
2019
期刊：
The journal of trauma and acute care surgery
影响因子：
0
作者：
Williams,AaronM;Bhatti,UmarF;Biesterveld,BenE;Graham,NathanJ;Chtraklin,Kiril;Zhou,Jing;Dennahy,IsabelS;Kathawate,RanganathG;Vercruysse,ClaireA;Russo,RachelM;Li,Yongqing;Alam,HasanB
通讯作者：
Alam,HasanB

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

DOI：
10.1016/j.jss.2021.04.014
发表时间：
2021-10
期刊：
The Journal of surgical research
影响因子：
0
作者：
Biesterveld BE;Siddiqui AZ;O'Connell RL;Remmer H;Williams AM;Shamshad A;Smith WM;Kemp MT;Wakam GK;Alam HB
通讯作者：
Alam HB

Valproic acid treatment rescues injured tissues after traumatic brain injury.

DOI：
10.1097/ta.0000000000002918
发表时间：
2020-12
期刊：
The journal of trauma and acute care surgery
影响因子：
0
作者：
Biesterveld BE;Pumiglia L;Iancu A;Shamshad AA;Remmer HA;Siddiqui AZ;O'Connell RL;Wakam GK;Kemp MT;Williams AM;Pai MP;Alam HB
通讯作者：
Alam HB