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将补充 他受过临床神经科学训练，有很强的细胞学和 发育神经生物学。培训将使他成为 一名独立调查员，在 神经病理学和细胞信号。弗吉尼亚大学，它的 在细胞信号研究方面获得内部认可的实力，是 拟议的项目，其长期目标是澄清 反应性星形细胞增多症的细胞内信号机制。 反应性星形细胞增多症是对神经的最显著的细胞反应。 系统损伤，这和免疫反应一样，可能既有好处 以及对功能恢复的不利影响。因此，这将是非常有意义的 了解星形胶质细胞激活的信号通路的重要性 反应，这样这个过程就可以在治疗上得到调节 神经疾病，从脊髓损伤到 神经退行性疾病。 几条平行的和相互连接的通路很可能调节 星形胶质细胞增多症；候选人的初步工作重点是 细胞外信号调节蛋白激酶/丝裂原活化蛋白激酶 (ERK/MAPK)途径，因为它代表了一个共同的效应因子 细胞外因素与星形胶质细胞增生症有关。ERK/MAPK被发现是 几种人类神经病理中反应性星形胶质细胞的高激活 各州。ERK/MAPK在反应性星形胶质细胞中高度激活 在几种人类神经病理状态下。此外，转基因小鼠 过度表达ERK/MAPK通路的特异性激活物c-Most， 表现出明显的反应性星形细胞增多症和神经功能障碍 与对照组小鼠比较。初步结果表明，ERK/MAPK是 转基因中星形胶质细胞亚群的组成性激活 与对照组小鼠相比。将在此测试的工作假说 该项目认为，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细胞表型。这个 具体目标针对系统的假设(目标1和目标3)和 细胞/分子(目标2)水平： 1)检测ERK/MAPK激活在四种小鼠模型中的必备作用 代表不同形式的暂时性和持续性星形胶质细胞 反应。 2)测试ERK/MAPK信号的充分性和必要性 星形胶质细胞在培养中的激活。 3)建立表达星形胶质细胞靶向激活剂的转基因小鼠 ERK/MAPK通路作为对工作假说的关键检验。

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.