Extracellular Matrix Mediates Axonal Integrity Following Brain Injury

细胞外基质介导脑损伤后轴突的完整性

• 批准号: 9247813
• 负责人: Linda L. Phillips
• 金额: $ 32.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247813
• 关键词: Action Potentials; Acute; Affect; Amyloid beta-Protein Precursor; Animals; Astrocytes; Attenuated; Axon; Behavioral; Binding; Biological Assay; Biological Preservation; Brain; Brain Injuries; CD44 gene; Cells; Cleaved cell; Cognitive deficits; Corpus Callosum; Data; Dissection; Electron Microscopy; Electrophysiology (science); Environment; Evolution; Extracellular Matrix; FK506; Fiber; Fostering; Gelatinases; Gliosis; Health; Human; Immune response; Immunohistochemistry; Immunosuppressive Agents; In Situ Hybridization; In Vitro; Inflammatory; Injury; Integrins; Internal Capsule; Knockout Mice; Link; Liquid substance; MMP2 gene; MMP9 gene; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Messenger RNA; Methods; Microglia; Minocycline; Modeling; Molecular; Neuroglia; Neuroprotective Agents; Olfactory Nerve; Outcome; Pathology; Pathway interactions; Patients; Percussion; Pharmaceutical Preparations; Pharmacology; Process; Proteins; Quantitative Reverse Transcriptase PCR; Rattus; Recovery; Rodent; Role; Signal Transduction; Simvastatin; Sister; Source; Stimulus; Tertiary Protein Structure; Testing; Time; Transcript; Traumatic Brain Injury; Up-Regulation; Western Blotting; axon injury; brain circuitry; cognitive testing; cytokine; environmental enrichment for laboratory animals; experimental study; functional outcomes; glial activation; in vivo; injured; loss of function; mRNA Expression; neurofascin; neuronal cell body; neuroprotection; novel; osteopontin; phosphacan; protein expression; public health relevance; receptor; receptor expression; repaired; response; response to injury; spatiotemporal; targeted treatment; white matter damage

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a significant U.S. health concern, with over 1.7 million new cases each year. Loss of brain circuitry underlies persistent cognitive deficits suffered by its victims, with axonal damage as a major contributor. Using the injured corpus callosum (CC) as a model, we have shown that postinjury change in matrix metalloproteinases (MMPs) is correlated with distinct myelinated and unmyelinated fiber pathology. MMPs are critical modulators of brain extracellular matrix (ECM) which affect axonal integrity. We found that CC gelatinases MMP2 and 9 peak in activity at different postinjury intervals which are marked by reactive glial response. We also observed that this MMP activity was temporally correlated with unmyelinated axon pathology. Treatment with neuroprotective compounds FK-506 and minocycline resulted in selective, time- dependent reduction of this gelatinase activity and reduced deficits in CC compound action potentials(CAPs). Pilot microarray studies revealed that osteopontin (OPN), a cytokine secreted into the ECM and reciprocally linked to MMP function, was significantly upregulated in injured CC. From these data we hypothesize that gelatinase response to traumatic axonal injury is mediated through acute activation of OPN within reactive glia. We also posit that the time course and glial role in this pathway will differ between unmyelinated and myelinated fibers. To test these hypotheses, the following aims will be explored in the fluid percussion model of TBI : 1) to document OPN/MMP2,9 during axonal injury within fiber environments enriched in unmyelinated (ON, olfactory nerve) and myelinated fibers (IC, internal capsule), and determine if OPN KO and MMP9KO alters these changes, 2) to dissect cell specific OPN/MMP2,9 interaction in vitro using primary CC and ON glial cultures, and 3) to test whether OPNKO or MMPKO alters efficacy of axonal neuroprotective drugs FK-506 and minocycline, then determine if combining optimal drug and OPN/MMP9 manipulation alters functional or structural outcome in the rat model of FPTBI. These studies are likely to identify novel options for regional and fiber targeted therapy in patients suffering from axonal damage after TBI.

描述（由申请人提供）：创伤性脑损伤（TBI）是美国一个重要的健康问题，每年有超过170万例新发病例。脑回路的丧失是受害者遭受持续认知缺陷的基础，轴突损伤是主要原因。使用受伤的胼胝体（CC）作为一个模型，我们已经表明，在基质金属蛋白酶（MMPs）损伤后的变化与不同的有髓和无髓纤维病理。基质金属蛋白酶是脑细胞外基质（ECM）的重要调节剂，影响轴突的完整性。我们发现，CC明胶酶MMP 2和9的活性峰值在不同的损伤后的时间间隔，标志着反应性胶质反应。我们还观察到，这种MMP活性与无髓轴突病理学在时间上相关。用神经保护化合物FK-506和米诺环素处理导致该明胶酶活性的选择性、时间依赖性降低和CC复合动作电位（CAP）的减少。试点微阵列研究表明，骨桥蛋白（OPN）是一种分泌到ECM中并与MMP功能相互关联的细胞因子，在损伤的CC中显着上调。从这些数据中，我们假设明胶酶对创伤性轴突损伤的反应是通过反应性胶质细胞内OPN的急性激活介导的。我们还证实，在无髓和有髓纤维之间，神经胶质细胞在这一通路中的作用和时间进程是不同的。为了检验这些假设，将在TBI的流体冲击模型中探索以下目标：1）记录在轴突损伤期间在富含无髓鞘的纤维环境中的OPN/MMP 2，9（ON，嗅神经）和有髓纤维（IC，内囊），并确定OPN KO和MMP 9 KO是否改变这些变化，2）解剖细胞特异性OPN/MMP 2，9使用原代CC和ON神经胶质培养物的体外相互作用，和3）测试OPNKO或MMPKO是否改变轴突神经保护药物FK-506和米诺环素的功效，然后确定组合最佳药物和OPN/MMP 9操纵是否改变FPTBI大鼠模型中的功能或结构结果。这些研究有可能为TBI后轴突损伤患者的区域和纤维靶向治疗确定新的选择。

项目成果

The effects of cyclosporin-A on axonal conduction deficits following traumatic brain injury in adult rats.

• DOI: 10.1016/j.expneurol.2010.03.026
• 发表时间: 2010-07
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Colley, Beverly S.;Phillips, Linda L.;Reeves, Thomas M.
• 通讯作者: Reeves, Thomas M.

Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury.

• DOI: 10.1016/j.expneurol.2016.06.011
• 发表时间: 2016-09
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Reeves TM;Trimmer PA;Colley BS;Phillips LL
• 通讯作者: Phillips LL