Using NAD+ precursor for treatment of global cerebral ischemia

利用NAD前体治疗全脑缺血

基本信息

批准号：
10622615
负责人：
TIBOR KRISTIAN
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622615
关键词：
Acute Brain Injuries Affect Animal Model Animals Balan Bioenergetics Brain Brain Injuries Catabolism Cell Death Cell Death Process Cerebral Ischemia Clinical Cognitive Complex Consumption Data Deacetylase Deacetylation Death Rate Dose Emotional Enzymes Estrous Cycle Failure Female Generations Glutamate-ammonia-ligase adenylyltransferase Goals Grant Heart Arrest Histologic Impairment Injury Ischemia Ischemic Brain Injury Metabolism Mitochondria Mitochondrial Proteins Mus Myocardial Infarction Nerve Degeneration Neurologic Neurological outcome Neurons Nicotinamide Mononucleotide Pathologic Pathway interactions Pilot Projects Poly Adenosine Diphosphate Ribose Post-Translational Protein Processing Process Production Prosencephalon Protein Acetylation Proteins Protocols documentation Publishing Reaction Recovery Regulation Research Role SIRT1 gene Sirtuins Stroke Survivors Testing Therapeutic Time Transgenic Animals Treatment Efficacy Treatment Protocols Work aged aging population brain cell cell type clinical application cofactor cognitive testing effective therapy effectiveness evaluation efficacy evaluation improved inhibitor insight knockout animal male neuron loss neuroprotection pre-clinical research preservation protective effect protein expression psychologic stroke outcome stroke victims therapy development tool treatment strategy

项目摘要

Summary: Ischemic brain damage due to cardiac arrest or stroke is one of the most complex pathophysiologic processes. To successfully treat ischemic brain injury, one need to target several cellular pathways and cell-type within the brain. NAD+ is an essential cofactor involved in multiple bioenergetic reactions and its degradation after ischemia leads to pathologic cellular metabolism and inhibition of energy production. The majority of cellular NAD+ is re-synthetized via the salvage pathway, where nicotinamide mononucleotide (NMN) is converted to NAD+. Our recent studies demonstrated that administration of NMN dramatically ameliorates ischemic brain injury following transient global cerebral ischemia. Furthermore, NMN treatment inhibited post-ischemic NAD+ catabolism, reduced poly-ADP-ribose generation, and reversed the excessive mitochondrial fragmentation. Finally, the ischemia-induced changes in mitochondrial protein acetylation were inhibited in NMN injected animals. Overall goal of this proposed project is to develop the most effective treatment strategy utilizing NMN that will dramatically reduce ischemic brain damage and characterize the mechanism of its neuroprotection. We hypothesize that NMN administration after ischemia will significantly inhibit neurodegeneration due to its multi-targeted effect and ability to improve mitochondrial functions and cellular bioenergetics. Specific Aim 1 is focused on the NMN-induced protein acetylation mechanisms that modulate mitochondrial dynamics and function. The role of Sirt1 and Sirt3 dependent deacetylation in mitochondrial fusion and fission will be determined using our transgenic animal models that concomitantly express mitochondria targeted eYFP and Sirt1 or Sirt3. Additionally, SIRT1, and SIRT3 knockout animals will be used as tools for inhibition of deacetylase activity. In specific Aim 2, we will perform time-dependent studies of NMN administration following global cerebral ischemia in mice. We will use unbiased stereological quantification of neuronal cell death, and multiple cognitive tests will be performed to assess the efficacy of treatment. The recovery periods will vary from 7 days up to 6 months after ischemic insult. In specific Aim 3, we will determine the neuroprotective effect of the NMN treatment by using the most neuroprotective protocol determined in Aim 2 on female and aged animals. The significance of this work is that it proposes to identify NMN as a protective compound that will significantly impact the clinical application of NAD+ precursors as therapeutic compounds for acute brain injury and potentially reveal new targets for neuroprotection.

概括：心脏骤停或中风引起的缺血性脑损伤是最复杂的病理生理之一过程。为了成功治疗缺血性脑损伤，需要靶向几个细胞途径和大脑中的细胞类型。 NAD+是参与多种生物能反应及其降解的必不可少的辅助因子缺血导致病理性细胞代谢并抑制能量产生。多数细胞NAD+通过打捞途径重新定位，其中烟酰胺单核苷酸（NMN）转换为nad+。我们最近的研究表明，NMN的给药很大瞬时全球脑缺血后，可以改善缺血性脑损伤。此外，NMN 治疗抑制了缺血后NAD+分解代谢，降低了多ADP-核糖的产生，并逆转线粒体碎片过多。最后，缺血诱导的线粒体变化 NMN注射的动物抑制蛋白乙酰化。这个拟议项目的总体目标是使用NMN制定最有效的治疗策略，该策略将大大减少缺血性大脑损害并表征其神经保护的机制。我们假设NMN 缺血后的给药将显着抑制神经退行性因素的多目标作用以及改善线粒体功能和细胞生物能学的能力。特定的目标1集中于调节NMN诱导的蛋白乙酰化机制线粒体动力学和功能。 SIRT1和SIRT3依赖性脱乙酰基的作用在线粒体融合和裂变将使用我们的转基因动物模型确定同时表达线粒体靶向EYFP和SIRT1或SIRT3。另外，SIRT1和SIRT3 敲除动物将用作抑制脱乙酰基酶活性的工具。在特定的目标2中，我们将在小鼠全球脑缺血后，对NMN给药的时间依赖性研究。我们将使用神经元细胞死亡的公正的立体定量定量，多个认知测试将是进行评估治疗的功效。恢复期限从7天到6 缺血性侮辱几个月后。在特定目标3中，我们将确定NMN的神经保护作用通过使用针对女性和老年动物的目标2确定的最神经保护方案的治疗。这项工作的意义在于，它建议将NMN识别为一种保护性化合物将显着影响NAD+前体作为急性治疗化合物的临床应用脑损伤并有可能揭示神经保护的新靶标。