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The role of mitochondrial fission in TBI outcome

线粒体裂变在 TBI 结果中的作用

基本信息

批准号：
9767293
负责人：
PRAMOD K DASH
金额：
$ 42.14万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767293
关键词：
Acute Address Animals Apoptosis Area Astrocytes Attenuated Bioenergetics Brain Brain Injuries Brain region Calcium Cell Death Cells Cessation of life Characteristics Clinical Research Cognitive Complement Crista ampullaris Cryoelectron Microscopy DNA Damage Dose Dynamin Enterobacteria phage P1 Cre recombinase Equilibrium Excision Failure Fatigue Female Functional disorder Glucose Guanosine Triphosphate Phosphohydrolases Health Hippocampus (Brain)Human Impaired cognition Impairment Independent Living Injury Investigation Lead Learning Length Life Link Location Long-Term Potentiation Measures Memory Memory impairment Metabolic Metabolic dysfunction Methods Mitochondria Mitochondrial Proteins Morphology Mus Mutant Strains Mice Nerve Degeneration Neurons Occupations Optics Organ Organelles Outcome Outer Mitochondrial Membrane Oxygen Pathologic Pathology Patient-Focused Outcomes Patients Peptides Play Positioning Attribute Process Production Proteins Public Health Reactive Oxygen Species Reporter Research Respiration Role Secondary to Shapes Structure Synapses Synaptic plasticity Synaptosomes Temporal Lobe Testing Therapeutic Time Tissue imaging Traumatic Brain Injury United States Widow Width base behavioral impairment cell type cognitive function conditional mutant confocal imaging density discrete time experimental study frontal lobe genetic regulatory protein improved innovation insight male morphometry neuron apoptosis neuron loss novel repaired segregation targeted treatment

项目摘要

Abstract Traumatic brain injury (TBI) remains a serious health concern in the United States, with nearly one out of every 225 people suffering a brain injury each year. The frontal and temporal lobes are highly vulnerable to TBI and damage to these areas presents a myriad of cognitive and behavioral impairments including learning and memory dysfunction. Problems with memory can interfere with keeping a job, planning one's day-to-day activities, and living an independent life. Memory impairments from TBI can result from death and dysfunction of cells resident to the hippocampus (a structure that resides in the core of the temporal lobe) and other brain structures. Both clinical and experimental studies have shown that metabolic dysfunction and lack of energy production in the injured brain contribute to secondary injury, hinders repair and gives rise to poor outcome. Mitochondria are the “energy powerhouses” of cells and have been recently shown to be highly dynamic. They constantly combine (i.e. fusion) and divide (i.e. fission) based on the energy needs of the cell. Mitochondrial fusion is regulated by the mitochondrial GTPases optic atrophy1 (Opa1) and mitofusin (Mfn)1/2, while fission is primarily regulated by the cytosolic GTPase dynamin-related protein1 (Drp1). In healthy cells, these two processes exist in a dynamic equilibrium. Excessive mitochondrial fission caused by aberrant Drp1 activity diminishes the ability of mitochondria to produce sufficient energy and has been implicated in cell death, dysfunction and neurodegeneration. The proposed research aims to investigate if altered mitochondrial dynamics plays a causal role in the neuronal pathology and poor outcome after TBI. We hypothesize that TBI increases mitochondrial fission for a discrete time widow following injury and that attenuating fission during this period will enhance mitochondrial function, decrease neuronal damage and improve cognitive function. Three Specific Aims have been proposed: Aim 1. To determine the time course for changes in mitochondrial dynamics and function following TBI in male and female mice. Aim 2. To determine cell-specific changes in mitochondrial morphology after TBI. Aim 3. Investigate if decreasing mitochondrial fission following TBI reduces neuronal loss and improves memory function. By investigating pathological changes in mitochondrial dynamics and function, these studies will provide an innovative perspective on mechanisms of metabolic dysfunction that occurs both in experimental TBI and human patients, and may lead to novel mitochondrial- targeted therapeutic approaches to improve patient outcome.

抽象的创伤性脑损伤 (TBI) 在美国仍然是一个严重的健康问题，几乎每人中就有一个每年有 225 人遭受脑损伤。额叶和颞叶非常容易受到 TBI 的影响这些区域的损害会带来多种认知和行为障碍，包括学习和记忆功能障碍。记忆力问题可能会影响保住工作、规划日常生活活动，独立生活。 TBI 造成的记忆障碍可能会导致死亡和功能障碍驻留在海马体（位于颞叶核心的结构）和其他大脑的细胞结构。临床和实验研究均表明代谢功能障碍和能量缺乏受伤大脑中的产生会导致继发性损伤，阻碍修复并导致不良结果。线粒体是细胞的“能量发源地”，最近被证明具有高度动态性。他们根据细胞的能量需求不断结合（即融合）和分裂（即裂变）。线粒体融合由线粒体 GTP 酶视神经萎缩 1 (Opa1) 和线粒体融合蛋白 (Mfn)1/2 调节，而裂变则受主要受胞质 GTP 酶动力相关蛋白 1 (Drp1) 调节。在健康细胞中，这两个过程处于动态平衡状态。 Drp1 活性异常导致线粒体过度分裂降低线粒体产生足够能量的能力，并与细胞死亡有关，功能障碍和神经变性。拟议的研究旨在调查线粒体是否发生改变动力学在 TBI 后的神经元病理学和不良预后中起着因果作用。我们假设 TBI 在受伤后的离散时间窗口内增加线粒体裂变，并在此期间减弱裂变期间将增强线粒体功能，减少神经元损伤并改善认知功能。三已提出具体目标：目标 1. 确定线粒体动力学变化的时间过程以及雄性和雌性小鼠 TBI 后的功能。目标 2. 确定细胞特异性变化 TBI 后线粒体形态。目标 3. 研究 TBI 后线粒体裂变是否减少减少神经元损失并改善记忆功能。通过研究线粒体的病理变化动力学和功能，这些研究将为代谢机制提供创新视角实验性 TBI 和人类患者中都会发生功能障碍，并可能导致新的线粒体- 有针对性的治疗方法，以改善患者的治疗效果。