Modulation of Acetylation in the Treatment of Lethal Hemorrhagic Shock

乙酰化的调节在致死性失血性休克的治疗中

• 批准号: 8245755
• 负责人: HASAN B ALAM
• 金额: $ 8.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2012-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245755
• 关键词: Acetylation; Attenuated; Cause of Death; Cell physiology; Cells; Dose; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Goals; Health; Hemorrhage; Hemorrhagic Shock; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Liquid substance; Lysine; Methods; Nuclear; Organ; Outcome; Pathway interactions; Play; Protein Acetylation; Proteins; Regulation; Regulator Genes; Research; Resuscitation; Role; Time; Translating; Trauma; cell injury; clinical practice; combat; improved; novel strategies; protective effect; treatment strategy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：出血是平民和战斗创伤中死亡的主要原因，有效的复苏策略有可能挽救许多生命。但是，常规复苏会加剧由出血性休克引起的细胞损伤。在亚细胞水平上，出血性休克和复苏可以改变基因表达，并损害随后的下游生存途径的调节。核组蛋白蛋白是已知的基因转录调节剂，我们先前已经表明，用组蛋白脱乙酰基酶抑制剂（HDACI）治疗通过多种裂解蛋白残基（“表观遗传调节”）在多种裂解蛋白残基上的特异性高乙酰化来增强基因转录，并​​改善肠肠丧失后生存的早期生存。新兴的证据还表明，非固定蛋白的乙酰化在细胞过程中可能同样重要，而与转录无关。因此，施用HDACI（有或没有常规的液体复苏）似乎是治疗致命出血的非常有前途的策略。但是，在将这些令人兴奋的发现可以转化为临床实践之前，必须清楚地鉴定出最有效的HDACI治疗方法（例如，代理，剂量和时间），确切的作用机制必须清楚地鉴定出来。长期目标：制定策略，以最大程度地减少细胞损伤并改善致命出血后的生存率。具体目标1：确定在致死性非反应出血后给予最明显的乙酰化的组蛋白脱乙酰基酶抑制剂（HDACI）处理？子目标1：确定最佳HDACI剂量以实现最大蛋白质乙酰化。子目标2：通过重复给予HDACI，确定蛋白质高乙酰化是否可以在更长的时间内维持。子目标3：确定来自不同HDACI基团的药物是否可以增强蛋白质乙酰化。具体目标2：确定在复苏液中添加HDACI是否有利吗？子目标1：确定在常规液中添加HDACI是否会减轻细胞损伤的标志并改善生存率？子目标2：确定是否可以将HDACI治疗与高渗液复苏相结合以实现协同作用？特定目的3：确定负责发挥HDACI保护作用的主要机制。子目标1：确定其转录会因组蛋白的乙酰化而改变的基因（“表观遗传机制”），并研究其对下游蛋白的影响。子目标2：确定HDACI的保护作用是否是由于非固定蛋白的直接乙酰化引起的。公共卫生相关性：证明是无效的常规治疗大规模失血方法，甚至可能会恶化结果。我们的研究表明，通过增强细胞中自然存在的基本保护机制，可以大大改善生存。我们项目的目的是完善这种新颖的方法，并制定有效治疗致命失血的策略。