CNS DEFECT IN A MURINE ZELLWEGER SYNDROME MODEL

描述（来自申请人摘要的逐字）：齐薇格综合征是一种 导致神经元异常人过氧化物酶体生物发生障碍 CNS中的迁移和严重的神经功能障碍。校长 研究者已经通过靶向的方法建立了这种疾病的鼠模型， PEX 2过氧化物酶体基因的缺失，并已证明存在 过氧化物酶体缺陷和大脑皮质异常。 出生后存活的PEX 2缺陷小鼠也会出现严重的 小脑异常在一个近交系中，PEX 2小鼠似乎发展出 广泛的神经元变性，在下丘脑有明显的集中 橄榄核这些小鼠提供了一个重要的动物模型，以了解 过氧化物酶体功能在CNS发育中的作用。主要研究者 提出了一系列细胞和分子的综合研究，开始， 回答以下问题。1.过氧化物酶体的作用是什么 缺乏对神经元增殖、迁移、存活和分化的影响 在小鼠中枢神经系统发育过程中？神经元前体细胞将在体内被标记 有丝分裂标记或逆转录病毒感染及其增殖率， 随后的迁移和最后的分化检查。研究者将 通过视频直接可视化体外迁移神经元的动力学 用培养的脑切片进行显微镜检查。发生在 将用细胞类型特异性标记物检查突变的大脑，所述细胞类型特异性标记物具有 建立了发展模式，以确定发病和演变的 过氧化物酶体疾病过程。超微结构研究将进一步确定 细胞类型特异性过氧化物酶体病理学观察在不同阶段的 发展过氧化物酶体缺乏对神经元存活和存活的影响 将研究迁移后的分化。2.细胞的作用是什么 自主功能与表观遗传因素在导致发育 缺陷？将采用两个主要战略来处理这一问题， 包括：a.正常或过氧化物酶体缺陷神经元体内移植 正常或突变的发育皮层。这些研究将 评估是否在大脑中观察到过氧化物酶体的细胞缺陷 缺陷神经元是神经元固有的，而不是继发于神经元的缺陷。 其他脑细胞和/或环境改变;和B.肝/肠特异性 PEX 2转基因表达以纠正肝过氧化物酶体异常， 评估循环毒性因子和/或营养不良的作用， 从肝功能障碍与内在脑代谢导致中枢神经系统 缺陷

DESCRIPTION (Verbatim from the Applicant's Abstract): Zellweger syndrome is a human peroxisomal biogenesis disorder that results in abnormal neuronal migrations in the CNS and severe neurologic dysfunction. The principal investigator has developed a murine model for this disorder by targeted deletion of the PEX2 peroxisomal gene and has demonstrated the presence of peroxisomal defects and a cerebral cortical abnormality in newborn mice. PEX2-deficient mice that survive in the postnatal period also develop severe cerebellar abnormalities. In an inbred strain, PEX2 mice appear to develop extensive neuronal lipidosis, with a prominent concentration in the inferior olivary nucleus. These mice provide an important animal model to understand the role of peroxisomal function during CNS development. The principal investigator proposes an integrated series of cellular and molecular studies to begin to answer the following questions. 1. What is the effect of the peroxisomal deficiency on neuronal proliferation, migration, survival, and differentiation during murine CNS development? Neuronal precursor cells will be labeled in vivo with mitotic markers or retroviral infection and their proliferative rate, subsequent migration and final differentiation examined. The investigator will directly visualize the dynamics of migrating neurons in vitro by video microscopy using cultured brain slices. The architectural changes that occur in the mutant brains will be examined with cell type specific markers having established developmental patterns to define the onset and the evolution of the peroxisomal disease process. Ultrastructural studies will define further the cell type specific peroxisomal pathology observed at various stages of development. The effect of peroxisomal deficiency on neuronal survival and postmigratory differentiation will be examined. 2. What is the role of cell autonomous function versus epigenetic factors in causing the developmental defects? Two major strategies will be used to approach this question and include: a. in vivo transplantation of normal or peroxisome-deficient neuronal progenitors into normal or mutant developing cortex. These studies will evaluate whether the cellular defects observed in the brain of peroxisome deficient neurons are intrinsic to the neurons versus secondary to defects in other brain cells and/or environmental alterations; and b. liver/gut specific PEX2 transgene expression to correct hepatic peroxisomal abnormalities and evaluate the role of circulating toxic factors and/or malnutritions that result from hepatic dysfunction versus intrinsic brain metabolism in causing the CNS defects.