NAD catabolism and mitochondrial dysfunction in acute neurodegenerative disease

急性神经退行性疾病中 NAD 分解代谢和线粒体功能障碍

• 批准号: 8043311
• 负责人: TIBOR KRISTIAN
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043311
• 关键词: ADP-ribosyl Cyclase; Acute; Acute Brain Injuries; Address; Age; Animals; Astrocytes; Bioenergetics; Blood; Body Temperature; Brain; Brain Injuries; Catabolism; Cause of Death; Cell Culture Techniques; Cell Death; Cerebrovascular Circulation; Chronic; Clinical; Cognitive; Data; Dose; Energy Metabolism; Enzyme Inhibition; Enzymes; Failure; Feeds; Fluorescence; Functional disorder; Genes; Glucose; Goals; Grant; Heart Arrest; High Prevalence; Hydrolysis; Impairment; Injury; Ischemia; Ischemic Brain Injury; Knockout Mice; Light; Long-Term Care; Mitochondria; Monitor; NAD+ Nucleosidase; NADP; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurological outcome; Neurons; Nicotinamide Mononucleotide; Nicotine; Outcome; Oxygen; Pathologic; Pathology; Pathway interactions; Permeability; Play; Population; Process; Prosencephalon; Proteins; Reaction Time; Recovery; Relative (related person); Reperfusion Therapy; Research; Risk Factors; Role; Stroke; Stroke prevention; Study Subject; Survivors; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Animals; Traumatic Brain Injury; Veterans; Work; acute stroke; brain tissue; cell type; clinical application; deprivation; design; disability; improved; in vivo; innovation; knockout animal; mitochondrial dysfunction; novel; novel therapeutic intervention; prevent; protective effect; pyridine nucleotide; respiratory; riboside; therapy development; translational approach

DESCRIPTION (provided by applicant): Impairments in mitochondrial functions have been frequently implicated in ischemic brain injury associated with stroke or cardiac arrest. However, the extent to which mitochondrial dysfunction in neurons and glia contribute to neurodegeneration is unknown and the mechanisms leading to mitochondrial failure are elusive. Mitochondrial impairment can result from activation of the permeability transition pore or excessive mitochondrial fission leading to loss of matrix pyridine nucleotides (NAD+, NADP+) and consequent detrimental NAD+ catabolism. We hypothesize that the major cellular NAD-regulating enzyme CD38 can significantly contributes to intracellular NAD+ hydrolysis following an ischemic insult and that inhibition of this enzyme will dramatically ameliorate the ischemic brain injury. This notion is strongly supported by our preliminary data that suggest promising protection against ischemic brain damage by nicotinamide mononucleotide (NMN), a naturally occurring compound that inhibits CD38 NAD+ glycohydrolase and also feeds into the NAD+ salvage pathway. The primary goal of this study is to determine whether pathologic morphological changes of neuronal or astrocytic mitochondria precedes brain tissue NAD+ depletion and, whether neuronal or astrocytic activity of CD38 is a major contributor to NAD+ hydrolysis following ischemia. To address these questions we propose to: 1. Utilize our unique transgenic animals that express fluorescent marker proteins specific either to neuronal or to astrocytic mitochondria. These animals will be used to quantify mitochondrial morphometric alterations specifically in neurons or astrocytes in brain. 2. To determine the specific role of CD38 in post-insult NAD+ catabolism we will utilize a CD38-null mice. The role of CD38 in cell death of astrocytes and neurons will be examined by exposing the pure neuronal and astrocytic cell culture to oxygen/glucose deprivation and by subjecting CD38 deficient animals to transient forebrain ischemia. 3. Examine the mechanisms of NMN protection against ischemic damage. We will perform both dose-dependent and time-effect studies with NMN administration following ischemic insult. After the designated recovery period, the histological and neurological outcome will be examined. The significance of this work is that it proposes both mechanistic and translational approaches to unravel the mechanisms of neuronal and astrocytic NAD+ catabolism and determine its role in acute brain injury. Furthermore, the identification of NMN protective mechanisms will significantly impact the clinical application of NAD+ precursors as therapeutic compounds for acute brain injury as stroke and TBI or chronic neurodegenerative disease. PUBLIC HEALTH RELEVANCE: With the high prevalence of stroke risk factors among veterans, including age, it is not surprising that stroke is extremely common in this population, with approximately 40,000 strokes per year. Stroke is the 3rd leading cause of death and the leading cause of disability in the US, placing a great demand on VA to provide disability and long-term care. Although there have been advances in stroke prevention, there is still a great need for new therapies to improve the outcomes of both acute stroke survivors and veterans with physical and cognitive disabilities after stroke. By focusing on understanding injury mechanisms that leads to mitochondrial and ultimately cellular bioenergetic failure, the research in this grant will promote the development of treatments with the ability to improve the long-term clinical outcome for stroke victims. Since cell death mechanisms triggered by stroke are very similar to those causing brain damage due to traumatic brain injury, the new therapeutic approaches studied in this project will also have significant implication for treatment of TBI victims.

描述（由申请人提供）：