GENETIC ANALYSIS OF NEURAL SAPK SCAFFOLD

描述(逐字摘自申请者摘要)：MAP激活级联 在真核细胞中的功能，将细胞外信号转译为 细胞生物学反应。MAPK包括应激激活的蛋白激酶 (SAPKs)，可调节细胞形状、细胞凋亡和神经肌肉 协调。FIP是一种新分离的SAPK支架蛋白，表达于 具有与成纤维细胞生长结合的特殊性质的神经元 因子同源蛋白(FHFs)。与FHF-2结合使用，FIP可以 协调上游激酶对SAPK4/p38 Delta的特异性激活 MLK-3。因此，虽然FHFs在结构上与成纤维细胞生长因子有关， 假设FHFs在细胞内作为SAPK激酶的一部分发挥作用。 神经细胞中的信号模块。 建议进行一系列的小鼠遗传学实验，以研究 FIP的神经生物学功能及其对FHFs的依赖 SAPK4/p38Delta激活。这些实验包括(I)生成和 FIP基因缺陷小鼠的分析，(II)FIP突变体的鉴定 结合FHF，以及(Iii)携带这种突变的小鼠的产生和分析 在FIP中。除了定义与以下各项相关的表型的重要性之外 破坏一种新的生化途径，这些研究可能会显著 提高我们对神经元发育的潜在机制的理解 功能。

DESCRIPTION (Verbatim from the Applicant's Abstract): Map kinase cascades function in eukaryotic cells to relay and translate extracellular signals into cellular biological responses. MAPKs include stress activated protein kinases (SAPKs) which can regulate cell shape, apoptosis, and neuromuscular coordination. FIP is a newly-isolated SAPK scaffold protein expressed in neuronal which has the unusual property of binding to fibroblast growth factor-homologous proteins (FHFs). In conjunction with FHF-2, FIP can coordinate the specific activation of SAPK4/p38delta by the upstream kinase MLK-3. Hence, while FHFs are structurally related to fibroblast growth factors, FHFs are hypothesized to function intracellularly as part of a SAPK kinase signalling module in neuronal cells. A series of mouse genetic experiments are proposed to investigate both the neurobiological function of FIP and its dependence upon FHFs to mediate SAPK4/p38delta activation. These experiments include (I) generation and analysis of FIP-deficient mice, (II) identification of FIP mutants incapable of binding FHF, and (III) generation and analysis of mice carrying such a mutation in FIP. In addition to the importance of defining the phenotype associated with disruption of a new biochemical pathway, these studies may significantly improve our understanding of mechanisms underlying neuronal development and function.