MAP KINASE SIGNALING IN ASTROGLIAL REACTIONS

NINDS独立科学家奖将为候选人提供 在细胞和分子信号方面的高级培训， 他的临床神经科学训练和强大的细胞和 发育神经生物学培训将使他成为 一个独立的调查员，在接口的特殊利基 神经病理学和细胞信号传导。弗吉尼亚大学及其 在细胞信号传导研究方面具有内部公认的优势，是 拟议项目，其长期目标是阐明 反应性星形细胞增多症的细胞内信号传导机制。 反应性星形胶质细胞增多症是对神经毒性最突出的细胞反应。 系统损伤，像免疫反应一样， 和对功能恢复的不利影响。这将是伟大的 了解星形胶质细胞激活的信号通路的重要性 反应，因此该过程可以在治疗上进行调节， 神经系统疾病，从脊髓损伤到 神经退行性疾病 几个平行和相互关联的途径可能会调节 星形胶质细胞增生;候选人的初步工作集中在 细胞外信号调节激酶/丝裂原活化蛋白激酶 (ERK/MAPK）途径，因为它代表了一种常见的效应子， 与星形胶质细胞增生有关的细胞外因子。ERK/MAPK被发现是 在几种人类神经病理学中， states. ERK/MAPK在反应性星形胶质细胞中高度活化 处于几种人类神经病理状态此外， 过表达c-most，ERK/MAPK通路的特异性激活剂， 表现出明显的反应性星形细胞增多症和神经功能缺损， 与对照组小鼠比较。初步结果表明，ERK/MAPK是 在转基因中的星形胶质细胞亚群中组成性激活 与对照组小鼠相比。在这个实验中要检验的工作假设 ERK/MAPK通路的持续激活是必不可少的 用于诱导和维持反应性星形胶质细胞表型。的 具体目标针对系统的假设（目标1和3）， 细胞/分子（目标2）水平： 1)在四种小鼠模型中检测ERK/MAPK激活的强制性作用， 代表不同形式的短暂性和持续性星形胶质细胞 反应 2)为了验证ERK/MAPK信号通路在肿瘤发生中的充分性和必要性， 星形胶质细胞活化。 3)为了产生表达星形胶质细胞靶向激活剂的转基因小鼠， ERK/MAPK通路作为工作假设的关键测试。

The NINDS Independent Scientist Award will provide the candidate with advanced training in cellular and molecular signaling that will complement his clinical neuroscience training and strong background in cellular and developmental neurobiology. The training will lead to his establishment as an independent investigator, with a special niche at the interface of Neuropathology and Cell Signaling. The University of Virginia, with its internally recognized strength in cell signaling research, is ideal for the proposed project, the long-term goal of which is to elucidate intracellular signaling mechanisms underlying reactive astrocytosis. Reactive astrocytosis is the most prominent cellular response to nervous system injury, which, like the immune response, may have both beneficial and detrimental effects on functional recovery. It would thus be of great importance to understand the signaling pathways activated in astroglial reactions, so that the process can be therapeutically modulated in neurological disorders ranging from spinal cord injury to neurodegenerative diseases. Several parallel and interconnected pathways are likely to regulate astrogliosis; initial work by the candidate has focused on the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway because it represents a common effector of extracellular factors implicated in astrogliosis. ERK/MAPK was found to be highly activated in reactive astrocytes in several human neuropathological states. ERK/MAPK was found to be highly activated in reactive astrocytes in several human neuropathological states. Moreover, transgenic mice which over-express c-most, a specific activator of the ERK/MAPK pathway, exhibited marked reactive astrocytosis and neurologic deficits in comparison to control mice. Preliminary results suggest that ERK/MAPK is constitutively activated in subpopulations of astrocytes in the transgenes in comparison to control mice. The working hypothesis to be tested in this project is that sustained activation of the ERK/MAPK pathway is essential for the induction and maintenance of reactive astrocytic phenotypes. The specific aims address the hypothesis at the systems (aims 1 and 3) and cellular/molecular(aim 2) levels: 1) To test the obligatory role of ERK/MAPK activation in four mouse models representative of distinct forms of transient and persistent astroglial reaction. 2) To test the sufficiency and necessity of ERK/MAPK signaling for astrocyte activation in culture. 3) To generate transgenic mice expressing astrocyte-targeted activators of the ERK/MAPK pathway as critical tests of the working hypothesis.