OLIGODENDROCYTE DEATH IN CEREBRAL ISCHEMIA

脑缺血引起的少突胶质细胞死亡

基本信息

批准号：
7267769
负责人：
Mark Paul Goldberg
金额：
$ 33.55万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-10 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7267769
关键词：
AMPA Receptors Abbreviations Action Potentials Acute Adult Agonist Astrocytes Axon Biological Preservation Brain Calcium Calcium Channel Calpain Categories Cell Culture System Cerebral Ischemia Cerebrospinal Fluid Cerebrum Cessation of life Class Coculture Techniques Corpus Callosum Dihematoporphyrin Ether Disease Electron Microscopy Endothelial Cells Enzymes Funding Galactosylceramides Glucose Glutamate Receptor Green Fluorescent Proteins Hour Hydrogen Peroxide Hydroxyl Radical Hypoxia Imagery In Vitro Injury Ischemia JSTX spider toxin Kainic Acid Receptors Knock-out Measurement Mediating Membrane Microglia Microscopy Modeling Morphology Multiple Sclerosis Mus Neurons Nitric Oxide Signaling Pathway Oligodendroglia Oxygen Pathology Pathway interactions Perfusion Perinatal Brain Injury Peroxonitrite Pharmaceutical Preparations Polyamines Process Production Protective Agents Protein Overexpression Proteins Quinoxalines Reactive Oxygen Species Receptor Activation Role Slice Sodium Channel Source Specificity Spermine Stimulus Superoxide Dismutase Superoxides Testing Tetrodotoxin Therapeutic Transgenic Mice Trauma alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate base catalase cell type deprivation direct application excitotoxicity extracellular fluorophore galactocerebroside genetic manipulation glutathione peroxidase immunocytochemistry inhibitor/antagonist injured kainate morphometry nervous system disorder neuronal cell body novel research study response two-photon voltage white matter white matter injury

项目摘要

DESCRIPTION (provided by applicant): Cerebral white matter (WM) is damaged in many neurologic disorders, including focal ischemia, perinatal brain injury, trauma, and multiple sclerosis. During the previous funding period, we and others established that oligodendrocytes (OLs) are highly vulnerable to over activation of AMPA/kainate (AMPA/KA) glutamate receptors. Unexpectedly, we found that AMPA/KA antagonists during oxygen-glucose deprivation protect axons as well as OLs, in oligodendrocyte-axon co-cultures and in WM brain slices. Since isolated axons are not vulnerable to glutamate receptor activation, the mechanisms of excitotoxic axon injury remain unknown. We will examine the hypothesis that over activation of AMPA/KA receptors on oligodendrocytes during oxygen-glucose deprivation contributes to damage of myelinated axons, and this involves release of reactive oxygen species (ROS). We have developed two new models to study these cellular interactions (a) a cell culture system in which isolated axons and oligodendrocytes are much more vulnerable to hypoxic and excitotoxic insults than either cell type alone, and (b) an acute brain slice model which allows measurement of white matter conduction together with visualization of axon and oligodendrocyte morphology. Using these models we will determine the role of oligodendrocyte glutamate receptor activation in axon injury, and assess potential injury pathways involving reactive oxygen species. Results of these studies may suggest treatment approaches for diseases, which share common pathology in central white matter.

描述（由申请人提供）：许多神经系统疾病，包括局灶性缺血，围产期脑损伤，创伤和多发性硬化症，脑白质（WM）受损。在上一个资金期间，我们和其他人确定少突胶质细胞（OLS）非常容易受到过度激活AMPA/Kainate（AMPA/KA）谷氨酸受体。出乎意料的是，我们发现在氧气 - 葡萄糖剥夺期间的AMPA/KA拮抗剂可保护轴突和OLS，在少突胶质细胞 - 轴心共培养和WM脑切片中。由于分离的轴突不容易受到谷氨酸受体激活的影响，因此兴奋轴突损伤的机制仍然未知。我们将研究以下假设：在氧气葡萄糖剥夺期间，AMPA/KA受体在少突胶质细胞上的激活过度激活有助于髓鞘轴突的损害，这涉及释放反应性氧（ROS）。我们开发了两个新模型来研究这些细胞相互作用（a）细胞培养系统，其中孤立的轴突和少突胶质细胞比单独的细胞类型更容易受到低氧和兴奋性毒性损伤的影响，（b）急性脑切片模型，该模型允许对白质的轴突传导以及轴突和轴突的可视化型和少根胶质细胞学的可视化。使用这些模型，我们将确定少突胶质细胞谷氨酸受体激活在轴突损伤中的作用，并评估涉及活性氧的潜在损伤途径。这些研究的结果可能表明疾病的治疗方法在中枢白质中具有共同的病理。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Calcium-independent inhibitory G-protein signaling induces persistent presynaptic muting of hippocampal synapses.

DOI：
10.1523/jneurosci.4960-10.2011
发表时间：
2011-01-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Crawford DC;Chang CY;Hyrc KL;Mennerick S
通讯作者：
Mennerick S

Dysmyelinated axons in shiverer mice are highly vulnerable to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated toxicity.

DOI：
10.1016/j.brainres.2009.10.066
发表时间：
2010-01-14
期刊：
Brain research
影响因子：
2.9
作者：
Pitt D;Gonzales E;Cross AH;Goldberg MP
通讯作者：
Goldberg MP

Synthesis and properties of Asante Calcium Red--a novel family of long excitation wavelength calcium indicators.

DOI：
10.1016/j.ceca.2013.08.001
发表时间：
2013-10
期刊：
Cell calcium
影响因子：
4
作者：
Hyrc KL;Minta A;Escamilla PR;Chan PP;Meshik XA;Goldberg MP
通讯作者：
Goldberg MP

Oligodendrocyte degeneration and recovery after focal cerebral ischemia.

DOI：
10.1016/j.neuroscience.2010.04.070
发表时间：
2010-09-01
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
McIver, S. R.;Muccigrosso, M.;Gonzales, E. R.;Lee, J. M.;Roberts, M. S.;Sands, M. S.;Goldberg, M. P.
通讯作者：
Goldberg, M. P.

AMPA/kainate receptors mediate axonal morphological disruption in hypoxic white matter.

AMPA/红藻氨酸受体介导缺氧白质中轴突形态的破坏。