Cytokine mediated oligodendrocyte injury

描述：Vartanian博士建议研究 脑室周围白质软化症(PVL)的发病机制 全身或局部产生的细胞因子损伤发育中的少突胶质细胞 这种毒性是PVL的一个潜在的相关机制。他会的 关注干扰素-g对少突胶质细胞的毒性，即 被肿瘤坏死因子-α强化。在第一个具体目标中，瓦塔尼安博士建议 确定促炎细胞因子或内毒素对生存的影响 少突胶质细胞或其祖细胞。在整个项目中，他都在测试 少突胶质细胞作为祖细胞或成熟的少突胶质细胞生长，具有 认为祖细胞更容易受损的假设。他将延长 他对干扰素-g和肿瘤坏死因子-a作用的初步研究包括 IL-1b和IL-6的作用。他将开始设计和测试保护装置 这些实验的策略，使用受体免疫粘附素来竞争 细胞因子与少突胶质细胞或其祖细胞上的受体结合 细胞。他将量化细胞数量；凋亡量，使用几个 方法；以及有丝分裂的数量，使用BrdU。这些都很有趣 这两项研究的重点都是这些细胞在 围产期损害范例，以及减少细胞的保护性治疗 死亡。这些研究很重要，很可能会有效地完成。在……里面 第二个具体目标，Vartanian博士建议确定 星形胶质细胞、小胶质细胞、内皮细胞和单核/巨噬细胞作为介体 少突胶质细胞死亡。在这些实验中，他将测试 少突胶质细胞和其他细胞的细胞间接触引起不同的效应 在少突胶质细胞上。他将量化细胞数量、生存能力和 细胞凋亡。使用Transwell共培养系统，然后他将测试 来自小胶质细胞、星形胶质细胞、巨噬细胞或内皮细胞的条件培养液 细胞因子或脂多糖预处理会引起少突胶质细胞的改变。最后， 他将测试特定的细胞因子抑制剂或氧气抑制剂 与少突胶质细胞孵育的自由基可以阻断因子的作用 在这些效应器细胞的培养液中。在最后一个具体目标中，他说。 Vartanian将确定内毒素或细胞因子是否会导致 少突胶质细胞会导致少突胶质细胞死亡和髓鞘减少 当立体注射的时候。

DESCRIPTION: Dr. Vartanian proposes to investigate the pathophysiologic mechanism of periventricular leukomalacia (PVL), with an overall hypothesis that systemic or locally produced cytokines injure developing oligodendrocytes and that this toxicity is a potentially relevant mechanism in PVL. He will focus on the toxicity of interferon-g (IFN-g) to oligodendrocytes, which is potentiated by TNF-a. In the first specific aim, Dr. Vartanian proposes to determine the influence of pro-inflammatory cytokines or endotoxin on survival of oligodendrocytes or their progenitors. Throughout this project he tests oligodendrocytes grown as progenitors or as maturing oligodendrocytes, with the hypothesis that the progenitors are more susceptible to damage. He will extend his preliminary studies on the effects of IFN-g and TNF-a to include the effects of IL-1b and IL-6. He will begin to design and test protective strategies for these experiments, using receptor immunoadhesins to compete for cytokine binding to the receptors on the oligodendrocytes or their progenitor cells. He will quantify cell numbers; amount of apoptosis, using several approaches; and amount of mitogenesis, using BrdU. These are interesting studies, which focus both on the mechanism of death of these cells in a perinatal damage paradigm, and also on a protective therapy to reduce cell death. These studies are important and likely to be completed effectively. In the second specific aim, Dr. Vartanian proposes to determine the role of astrocytes, microglia, endothelial cells and monocytes/macrophages as mediators of oligodendrocyte cell death. In these experiments, he will test whether cell-cell contact of oligodendrocytes and other cells induces different effects on the oligodendrocytes. He will quantify cell number, viability, and apoptosis. Using a transwell coculture system, he will then test whether conditioned media from microglia, astrocytes, macrophages or endothelial cells pretreated with cytokines or LPS will induce oligodendrocytes changes. Lastly, he will test whether specific inhibitors of cytokines or inhibitors of oxygen free radicals incubated with the oligodendrocytes can block effects of factors in the medium from these effector cells. In the last specific aim, Dr. Vartanian will determine if endotoxin or cytokines that cause injury to oligodendrocytes will induce oligodendrocyte cell death and hypomyelination when injected stereotactically.