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Targeting mitostasis via activation of mitochondrial biogenesis after TBI

TBI 后通过激活线粒体生物发生来靶向有丝分裂

基本信息

批准号：
10656408
负责人：
Patrick G Sullivan
金额：
--
依托单位：
VA MEDICAL CENTER - LEXINGTON, KY
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656408
关键词：
Adult Animals Award Behavioral Bioenergetics Biogenesis Biological Assay Brain Brain Injuries Cell Count Cell physiology Cells Clinical Coupled Data Diagnosis Diet Dose Energy Metabolism FDA approved Female Glucose Grant Hippocampus Histologic Histology Homeostasis Impaired cognition Impairment Injury Intervention Ipsilateral Knockout Mice Label Link Liquid substance Magnetism Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Methods Military Personnel Mitochondria Mitochondrial DNA Modernization Molecular Mus Neurocognition Neurocognitive Neurons Outcome Measure PPAR gamma Pathogenesis Pathology Pathway interactions Performance Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pioglitazone Post-Traumatic Stress Disorders Process Production Proto-Oncogene Proteins c-akt Publishing Pyruvate Reactive Oxygen Species Receptor Signaling Regimen Resolution Sampling Services Signal Transduction Specificity Synapses TBI treatment Techniques Technology Testing Therapeutic Therapeutic Intervention Tissues Transgenic Mice Traumatic Brain Injury Treatment Efficacy Treatment Protocols Veterans War Work brain dysfunction central nervous system injury cognitive function cognitive recovery cohort controlled cortical impact dosage experience formoterol high risk population improved in vivo injured mRNA Expression male metabolomics military operation mitochondrial dysfunction mitochondrial metabolism molecular marker morris water maze neurobehavioral neurogenesis neuropathology novel novel strategies object recognition pharmacologic prevent primary outcome prophylactic protein expression receptor response stable isotope therapeutic target therapeutically effective treatment optimization white matter

项目摘要

Experience in contemporary military operations suggests that traumatic brain injury (TBI) is the signature injury of modern wars making our troops a high-risk population for TBI. Among the 327,388 OEF/OIF veterans using VA services in 2009, 6.7% were diagnosed with TBI of which 73% of those were diagnosed with posttraumatic stress disorder (PTSD). However, to date there is no approved treatment for TBI, in part due to an incomplete understanding of the pathobiology underlying TBI. Compelling experimental data demonstrate that mitochondrial dysfunction is a pivotal link in the neuropathological sequelae of brain injury. This premise comes from our published work (and that of others) demonstrating that loss of mitochondrial homeostasis and increased mitochondrial reactive oxygen species (ROS) production occurs following TBI. Protecting or restoring mitochondrial function by therapeutically targeting mitochondrial impairment improves neuronal function after TBI. Here, we propose a novel approach of activating mitochondrial biogenesis (MB), a necessary process in mitochondrial dynamics, after TBI using pharmacological intervention. Through MB, dysfunctional mitochondria are replaced via signaling networks involving peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC-1α) as a master regulator. Activation of MB can be an important intervention to modulate mitochondrial dynamics and prevent metabolic disruption after TBI. Recently, two drugs formoterol and lasmiditan have been screened by us and our collaborators and found to induce PGC-1α via activation of two independent receptors, β2-adrenoreceptor (β2AR) and 5-hydroxytryptamine1F (5-HT1F) respectively. We hypothesize that MB activation at the optimized drug dosage will improve mitochondrial function, mitigate pathology and restore cognitive function following TBI. To test this hypothesis, in Specific Aim 1, we will examine the temporal and spatial aspects of MB after TBI in the injured cortex and hippocampus by analyzing molecular markers of MB. We will also refine and establish the dose-response and therapeutic window of intervention for formoterol and lasmiditan treatment to optimize MB after TBI. In this Aim, we will also test the hypothesis that treatment with MB activators promotes cognitive recovery following TBI at the optimal therapeutic regime. In Specific Aim 2, we will assess cell- and tissue-specific changes in energy homeostasis following TBI and MB activation therapy using bioenergetic and metabolomic approaches and a novel approach to isolate synaptic mitochondria. We will also examine the underlying metabolic mechanisms of TBI and MB activation using in vivo and ex vivo 13C-labeled tracing followed by advanced stable isotope-resolved metabolomic analysis. Lastly, in Specific Aim 3 we will assess the specificity of MB activators on induction of MB after TBI. Using 5-HT1F/β2AR KO mice, we hypothesize that functional benefit is dependent on the specific receptor signaling leading to activation of MB. Overall, we hypothesize that optimizing the therapeutic window and dose response of these MB activators after TBI will lead to improved bioenergetic homeostasis and neurocognitive performance after TBI.

当代军事行动的经验表明，创伤性脑损伤（TBI）是典型的损伤

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.

LRP1缺乏对氧化应激的响应促进了线粒体：对脑损伤后线粒体靶向的影响。

DOI：
10.3390/cells12101445
发表时间：
2023-05-22
期刊：
CELLS
影响因子：
6
作者：
Velmurugan, Gopal V.;Hubbard, W. Brad;Prajapati, Paresh;Vekaria, Hemendra J.;Patel, Samir P.;Rabchevsky, Alexander G.;Sullivan, Patrick G.
通讯作者：
Sullivan, Patrick G.

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion.

DOI：
10.1093/braincomms/fcad032
发表时间：
2023
期刊：
Brain communications
影响因子：
4.8
作者：
通讯作者：

Targeting mitoNEET with pioglitazone for therapeutic neuroprotection after spinal cord injury.

DOI：
10.4103/1673-5374.219040
发表时间：
2017-11
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Rabchevsky AG;Patel SP;Sullivan PG
通讯作者：
Sullivan PG

A Mild Traumatic Brain Injury in Mice Produces Lasting Deficits in Brain Metabolism.

DOI：
10.1089/neu.2018.5663
发表时间：
2018-10-15
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Lyons DN;Vekaria H;Macheda T;Bakshi V;Powell DK;Gold BT;Lin AL;Sullivan PG;Bachstetter AD
通讯作者：
Bachstetter AD

Targeting mitochondrial dysfunction in CNS injury using Methylene Blue; still a magic bullet?

使用亚甲基蓝针对中枢神经系统损伤中的线粒体功能障碍；