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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：
10439887
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/10439887
关键词：
Acetylesterase 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 base brain cell cell type clinical application cofactor cognitive testing effective therapy effectiveness 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.

简介: