Neuroteratogenic Mechanism of LCM Virus Infection

描述（由申请人提供）：本研究事业奖旨在培养Daniel Bonthius博士成为一名独立的神经科学家。该奖项是为期三年的家长奖的两年延伸。Bonthius博士是一名儿科神经学家，对环境因素的不利影响特别感兴趣，包括先天性病毒感染，对胎儿大脑发育的影响。他的长期职业目标是成为一名能够在神经畸形学方面做出有意义贡献的内科科学家。他将重点研究分子神经生物学的研究技术，这是神经畸形学领域的关键。Bonthius博士将通过教学课程、技能研讨会、技术研讨会以及他对淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的神经畸形学的研究来获得他新的研究技能。LCMV是一种流行的病毒，可以严重损害发育中的人类胎儿大脑。新生儿大鼠脑内注射LCMV为人类先天性LCMV感染提供了一个良好的模型系统。Bonthius博士将利用这个模型系统来研究病毒感染的神经致畸机制。接种新生大鼠后，LCMV选择性地感染四个脑区，包括小脑、嗅球、海马和脑室周围区。在每一个区域，LCMV诱导独特的病理形式与独特的时间进程。在小脑中，LCMV诱导急性破坏过程，而在嗅球中，病毒诱导急性发育不全。在海马中，LCMV不会引起急性病理，但会导致齿状颗粒细胞延迟和严重的脱落。在心室周围区域，LCMV不会引起急性或迟发性病理。本研究的主要目的是确定这些不同病理变化的细胞和分子机制。参与病理过程的免疫细胞类型将被确定。将探讨细胞因子、趋化因子和一氧化氮过量产生的作用。该项目的第二个目标是探索α -三磷酸腺苷（α - dg）是LCMV的细胞受体的可能性。将α - dg的表达形态与LCMV感染的空间分布进行比较。a-DG在影响LCMV的趋向性和感染性中的重要性将通过在将脑切片暴露于LCMV之前用抗体阻断α - dg来检验。

DESCRIPTION (provided by applicant): This Research Career Award is a plan to foster the development of Dr. Daniel Bonthius into an independent neuroscientist. This Award is a two-year extension of a three-year parent Award. Dr. Bonthius is a pediatric neurologist with a special interest in the adverse effects of environmental agents, including congenital viral infections, on fetal brain development. His long-term career goal is to become a physician-scientist capable of making meaningful contributions in neuroteratology. The research techniques on which he will focus are those of molecular neurobiology, which are of key importance in the field of neuroteratology. Dr. Bonthius will acquire his new research skills through a combination of didactic courses, skills workshops, technical seminars, and through his research into the neuroteratology of lymphocytic choriomeningitis virus (LCMV) infection. LCMV is a prevalent virus, which can severely damage the developing human fetal brain. Injection of LCMV into the neonatal rat brain provides an excellent model system of human congenital LCMV infection. Dr. Bonthius will utilize this model system to study the neuroteratogenic mechanisms of the viral infection. Following inoculation of the neonatal rat, LCMV selectively infects four brain regions, which include the cerebellum, olfactory bulb, hippocampus, and periventricular region. In each of the four regions, LCMV induces unique forms of pathology with unique time courses. In the cerebellum, LCMV induces an acute destructive process, while in the olfactory bulb, the virus induces an acute hypoplasia. In the hippocampus, LCMV induces no acute pathology, but causes a delayed and severe dropout of dentate granule cells. In the periventricular region, LCMV induces no acute or delayed-onset pathology. The principal goal of this research is to identify the cellular and molecular mechanisms underlying these diverse pathologic changes. The types of immune cells involved in the pathologic processes will be identified. The role of cytokines, chemokines and nitric oxide overproduction will be explored. A second goal of the project is to explore the possibility that alpha-dystroglycan (alpha-DG) is the cellular receptor for LCMV. The topography of alpha-DG expression will be compared with the spatial distribution of LCMV infection. The importance of a-DG in influencing the tropism and infectivity of LCMV will be examined by blocking alpha-DG with an antibody prior to exposure of brain slices to LCMV.