Modulation of Acetylation in the Treatment of Lethal Injuries

乙酰化在致命伤害治疗中的调节

• 批准号: 9026879
• 负责人: HASAN B ALAM
• 金额: $ 31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026879
• 关键词: Acetylation; Address; Americas; Animal Experiments; Animal Model; Area; Biological Assay; Brain Injuries; Cause of Death; Cell Nucleus; Cell physiology; Cessation of life; Colon Injury; Cytosol; Data; Disease; Dose; Drug or chemical Tissue Distribution; Effectiveness; Epigenetic Process; Family suidae; Fresh Frozen Plasmas; Functional disorder; Funding; Gene Proteins; Genes; Goals; Grant; Hemorrhage; Hemorrhagic Shock; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Injury; Investigation; Lead; Life; Liquid substance; Methods; Military Personnel; Mitochondria; Modeling; Molecular; Nuclear; Organ; Pharmaceutical Preparations; Phase I Clinical Trials; Physiological; Protein Acetylation; Protein Isoforms; Proteins; Regimen; Research; Resuscitation; Rib Fractures; Rodent Model; Role; Sepsis; Series; Shock; Surgeon; Testing; Tissues; Toxic effect; Trauma; Traumatic Brain Injury; United States National Institutes of Health; Valproic Acid; Work; improved; improved outcome; in vivo; inhibitor/antagonist; injured; insight; liver injury; natural hypothermia; novel; novel strategies; protective effect; protein metabolism; public health relevance; research study; septic; soft tissue; tissue trauma

 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.

 描述（由申请人提供）：出血和脑损伤是平民和军事创伤中死亡的主要原因。目前的治疗大多是支持性的，并且不能解决由休克和损伤引起的特定细胞功能障碍，乙酰化正在迅速成为关键。调节众多基因表达（通过调节核组蛋白）以及多种非核蛋白功能的表观遗传机制在 NIH 拨款 R01GM84127 的资助下，我们已经证明了这种治疗方法。与非选择性组蛋白脱乙酰酶 (HDAC) 抑制剂（泛 HDACI）一起使用可以快速激活关键机制，从而提高致命性出血、脓毒症和联合损伤动物模型的生存率。这些结果使我们能够启动一个联邦政府资助的阶段 - I 泛 HDACI 丙戊酸的临床试验（ClinicalTrials.gov 标识符 NCT01951560）虽然令人兴奋，但非选择性 HDACI 治疗是令人兴奋的。 HDAC 的 18 种已知同工型具有非常独特的作用、组织分布和生理功能，而新的抑制剂具有更高的同工型选择性，因此更具疾病特异性。我们最近表明，在脓毒症模型中，使用亚型特异性 HDACI（iso-HDACI）治疗比泛 HDACI 更有效，初步数据表明这对于其他致命性损伤也可能是正确的。额外的研究，因为药物的适当选择至关重要，并且抑制错误的 HDAC 可能是不健康的。拟议的研究是我们之前工作的逻辑延伸，并将体内实验与细胞和分子测定相结合来识别。致命性损伤的新疗法，并为潜在机制提供重要见解：制定新策略，最大限度地减少细胞损伤并提高致命性损伤后的生存率。 具体目标 1：测试在简单情况下给予 iso-HDACIs 的有效性。致命的失血（无多重创伤）在啮齿动物模型中具体目标 2：确定在复苏方案中添加 iso-HDACI 是否会改善临床现实模型的结果，其中失血性休克因多器官损伤和多种微生物污染而复杂化。确定在两个不同物种中不同损伤后 iso-HDACI 产生多器官保护作用的主要机制 方法：我们的计划是进行一系列动物实验。首先，将使用简单失血的啮齿动物模型来比较 iso-HDACI 与 pan-HDACI，并了解各种 iso-HDACI 与其他有效的细胞保护策略之间的相互作用。然后，该模型中的结果将在出血、多种创伤和[来自多种微生物污染（结肠损伤）的组织]的临床现实猪模型中得到进一步验证。这些实验将用于阐明基因、蛋白质、代谢和重要细胞功能水平的潜在机制。