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Mitochondrial Sirtuin-3 dysregulation in epileptogenesis

癫痫发生中的线粒体 Sirtuin-3 失调

基本信息

批准号：
9385643
负责人：
MANISHA N PATEL
金额：
$ 4.82万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385643
关键词：
Acetylation Aging Animal Model Antioxidants Attenuated Bioenergetics Brain Cell physiology Chronic Comorbidity Complex Data Deacetylase Electroencephalography Enzymes Epilepsy Epileptogenesis Etiology Event Experimental Models Functional disorder Goals Homeostasis Impaired cognition Impairment Incidence Injury Knockout Mice Knowledge Lighting Link Mass Spectrum Analysis Mediator of activation protein Memory impairment Metabolic Metabolic Control Mitochondria Mitochondrial Proteins Modeling Monitor Mus NADH Nature Neurons Nicotinamide adenine dinucleotide Oxidation-Reduction Oxidative Stress Pathway interactions Pharmacology Post-Translational Protein Processing Production Prosencephalon Protein Acetylation Reactive Oxygen Species Research Role SOD2 gene Seizures Sirtuins Site Source Supplementation Temporal Lobe Epilepsy Testing Therapeutic age related base cognitive function cognitive testing human imaging imaging study improved infancy innovation insight interest mitochondrial dysfunction nervous system disorder neuron loss neuronal excitability novel novel therapeutic intervention programs public health relevance restoration

项目摘要

DESCRIPTION (provided by applicant): Mitochondria control critical cell functions that can impact epilepsy and its comorbidities. Key features of temporal lobe epilepsy (TLE) such as its progressive nature, rising incidence with aging and bioenergetic demands suggest mitochondrial involvement. Mitochondrial dysfunction has been implicated in various neurological diseases including experimental models of TLE. However, the precise mechanisms underlying mitochondrial dysfunction in TLE remain unclear. The proposal builds upon our previous discoveries of impaired mitochondrial redox status and bioenergetics in experimental models of TLE. A central mediator that links mitochondrial oxidative stress with bionenergetic dysfunction is sirtuin-3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase known to maintain metabolic homeostasis. SIRT3 is exquisitely sensitive to aging and serves as a major switch to regulate mitochondrial protein acetylation to control metabolic flux and energy. It is hypothesized that decreased SIRT3 activity and consequent increases in mitochondrial protein acetylation contribute to the impaired bioenergetics in TLE. Using novel mass spectrometry-based quantitative mitochondrial acetylomics, brain-specific SIRT3 conditional knockout mice and restorative therapies, we plan to explore the role of SIRT3 in TLE. Aim 1 will determine if SIRT3 dysfunction occurs following chemoconvulsant-induced epilepsy. Aim 2 will determine if conditional deletion of SIRT3 or its target, Sod2 is sufficient to cause age-related epilepsy and cognitive dysfunction and Aim 3 will determine if restoration of SIRT3 activity by supplementation with NAD+ precursor attenuates deficits observed in chemoconvulsant-induced TLE. Collectively, this project can identify a novel role of SIRT3 as a mediator of mitochondrial dysfunction in chronic seizures and/or cognitive impairment associated with TLE and provide a therapeutic approach for its treatment.