GENETIC ANALYSIS OF NEURAL SAPK SCAFFOLD

描述（来自申请人摘要的逐字）：Map激酶级联 在真核细胞中的功能是传递和翻译细胞外信号， 细胞生物学反应。MAPK包括应激活化蛋白激酶 （SAPKs），可以调节细胞形状，凋亡和神经肌肉 协同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不寻常特性的神经元 因子同源蛋白（FHF）。结合FHF-2，FIP可以 通过上游激酶协调SAPK 4/p38 δ的特异性激活 MLK-3因此，虽然FHF在结构上与成纤维细胞生长因子相关， 假设FHF作为SAPK激酶的一部分在细胞内起作用 神经元细胞中的信号模块。 提出了一系列小鼠遗传学实验来研究这两种情况。 FIP的神经生物学功能及其对FHF介导的依赖性 SAPK 4/p38 δ激活。这些实验包括（I）生成和 FIP缺陷小鼠的分析，（II）鉴定不能 结合FHF，和（III）产生和分析携带这种突变的小鼠 在FIP。除了定义与以下疾病相关的表型的重要性之外， 新的生化途径的破坏，这些研究可能会显着 提高我们对神经元发育机制的理解， 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.