IMMUNOPATHOLOGIC ALTERATIONS IN RHESUS MACAQUES WITH GLOBOID CELL LEUKODYSTROPHY

患有球状细胞脑白质营养不良的恒河猴的免疫病理学改变

• 批准号: 8358070
• 负责人: Bruce A. Bunnell
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358070
• 关键词: Affect; Age; Animals; Astrocytes; Brain; CCL2 gene; Cells; Data; Disease; Disease Progression; Funding; Gene Expression; Glial Fibrillary Acidic Protein; Globoid cell leukodystrophy; Grant; Inflammatory; Interleukin-1; Macaca; Macaca mulatta; Messenger RNA; Microglia; National Center for Research Resources; Peripheral Nervous System; Play; Primates; Principal Investigator; Process; Research; Research Infrastructure; Resources; Role; Sampling; Source; Staging; Therapeutic Intervention; Toll-like receptors; Tumor Necrosis Factor-alpha; United States National Institutes of Health; cost; cytokine; galactosylceramidase; human TNF protein; mind control; sex; synthetic polymer Bioplex; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Globoid cell leukodystrophy, or Krabbe's disease, is a severe disorder of the central and peripheral nervous system caused by the absence of galactocerebrosidase (GALC) activity. We have previously determined that rhesus macaques affected with Krabbe's disease demonstrated marked increases in the levels of expression of iNOS, TNF-alpha, and IL-1 in the affected white matter, colocalizing with globoid cells, activated microglia, and astrocytes. Cytokine mRNA levels revealed markedly increased gene expression of CCL2 in the brain of affected macaques. CCL2-expressing cells were detected throughout the affected white matter, colocalizing with GFAP cells and astrocytes. We are presently performing as complete analysis of cytokine alterations using a Bioplex analysis at various stages of disease progression. Krabbe brain white matter samples are being directly compared to age and sex matched control brain samples from unaffected animals. In addition, we have begun studies to investigate the role of the inflammatory processes on disease progression. We have generated data demonstrating a wave of altered expression of the Toll-like Receptors (TLRs) in the Krabbe brain. The altered expression correlates with the progression of the disease. It is hoped that this analysis will provide an in depth analysis in to the role that the inflammatory process plays in the disease progression and to identify potential targets for therapeutic intervention.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 球状细胞脑白质营养不良或克拉伯氏病是一种由于半乳糖脑苷酶 (GALC) 活性缺失引起的中枢和周围神经系统严重疾病。我们之前已经确定，患有克拉伯氏病的恒河猴在受影响的白质中表现出 iNOS、TNF-α 和 IL-1 的表达水平显着增加，与球状细胞、活化的小胶质细胞和星形胶质细胞共存。细胞因子 mRNA 水平显示受影响的猕猴大脑中 CCL2 基因表达显着增加。在受影响的白质中检测到表达 CCL2 的细胞，与 GFAP 细胞和星形胶质细胞共定位。我们目前正在疾病进展的各个阶段使用 Bioplex 分析对细胞因子的变化进行完整的分析。克拉布大脑白质样本与来自未受影响动物的年龄和性别匹配的对照大脑样本直接进行比较。此外，我们已经开始研究炎症过程对疾病进展的作用。我们生成的数据表明 Krabbe 大脑中 Toll 样受体 (TLR) 的表达发生了一波改变。表达的改变与疾病的进展相关。希望这项分析能够深入分析炎症过程在疾病进展中的作用，并确定治疗干预的潜在目标。