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（由适用提供）：出血和脑损伤是平民和军事创伤中死亡的主要原因。当前的疗法大部分受支持，并且不能解决因冲击和损伤引起的特定细胞功能障碍。乙酰化迅速成为一种关键的表观遗传机制，可调节许多基因的表达（通过调节核组蛋白）以及多种非核蛋白的功能。由NIH Grant R01GM84127资助，我们已经证明，非选择性组蛋白脱乙酰基酶（HDAC）抑制剂（PAN-HDACI）可以快速激活关键机制，从而改善了致命性出血模型的生存率，可改善致命性出血模型，SEPSIS和综合感染。这些结果使我们能够开始对泛HDACI，丙戊酸的联邦资助I期临床试验（Clinicaltrials.gov识别剂，尽管令人兴奋，但对非选择性HDACI的治疗并不是最佳的，因此对非常大剂量的需求并不是最佳的，这会产生对毒性的重要潜力。同工型选择性，因此我们最近表明，在化粪池模型中，使用同工型特定的HDACI（ISO-HDACI）更有效，而初步数据可能是对其他重要的侮辱，因为这可能是对药物的适当选择，因此，这也可能是对其他领域的态度。我们先前的工作，并将体内实验与细胞和分子测定法相结合，以确定致命感染的新处理，并为基础机制提供重要的见解，以开发出新的策略，以最小化细胞损害，并改善无致命性损失的损失。啮齿动物模型。针对三个特定目标的实验。 （结肠损伤）。