EICOSANOID IN GROWTH CONE REPELLENT SIGNALING

生长锥排斥信号中的二十烷酸

基本信息

批准号：
6825753
负责人：
KARL H PFENNINGER
金额：
$ 29.75万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-12-01 至 2006-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6825753
关键词：
biological signal transduction cell adhesion cell component structure /function cerebral cortex confocal scanning microscopy eicosanoids embryo /fetus tissue /cell culture fatty acid biosynthesis growth cones laboratory rat nerve /myelin protein neurogenesis neuronal guidance phospholipase A2 phosphorylation protein kinase C

项目摘要

The broad goals of the proposed program are to study mechanisms involved in axonal pathfinding during development and regeneration. Of specific interest is the signaling that translates a chemorepellent's action on the growth cone into collapse. Our data indicate that generation of eicosanoids by 12/15-lipoxygenase is necessary and sufficient (at least partially) for semaphorin 3A-induced collapse. Other results suggest that synthesis of these eicosanoids is part of a cascade involving, upstream, cytosolic phospholipases A2 (cPLA/2) and, downstream, protein kinase C (PKC) and adhesion site proteins, whose phosphorylation may trigger adhesion site disassembly and detachment. In a series of cell biological studies we will test the hypothesis that this pathway regulates detachment of the growth cone periphery during collapse. Experiments will be focused on the effects of semaphorin 3A. In cultures of responsive neurons we will study growth structure and adhesion. In isolated growth cone preparations enriched in the semaphorin 3A receptor, neurophilin-1, we will analyze cPLA2 activation, eicosanoid synthesis and PKC stimulation, as well as phosphorylation of adhesion site proteins. These studies are expected (i) to provide new insights into the little understood signalling mechanisms activated by repellants and (ii) to establish a novel signalling pathway that is believed to trigger disassembly of growth cone adhesion sites. The analysis of the mechanisms of growth cone pathfinding and repulsion is fundamental to our understanding of nervous system development, and insight into the action of chemorepellants on growth cones is likely to reveal new options for promoting nerve regeneration in the adult CNS.

拟议计划的主要目标是研究发育和再生过程中轴突寻路所涉及的机制。特别令人感兴趣的是将化学排斥剂对生长锥的作用转化为崩溃的信号。我们的数据表明，12/15-脂氧合酶产生类二十烷酸对于信号蛋白 3A 诱导的崩溃是必要且充分的（至少部分）。其他结果表明，这些类二十烷酸的合成是涉及上游胞质磷脂酶 A2 (cPLA/2) 和下游蛋白激酶 C (PKC) 和粘附位点蛋白的级联的一部分，其磷酸化可能会引发粘附位点分解和脱离。在一系列细胞生物学研究中，我们将检验这一假设：该途径在塌陷过程中调节生长锥外围的脱离。实验将集中于 semaphorin 3A 的作用。在反应神经元的培养中，我们将研究生长结构和粘附。在富含脑信号蛋白 3A 受体、神经亲和蛋白-1 的分离生长锥制剂中，我们将分析 cPLA2 激活、类二十烷酸合成和 PKC 刺激，以及粘附位点蛋白的磷酸化。这些研究预计（i）为驱避剂激活的鲜为人知的信号机制提供新的见解，以及（ii）建立一种新的信号传导途径，据信可以触发生长锥粘附位点的分解。对生长锥寻路和排斥机制的分析是我们理解神经系统发育的基础，深入了解化学排斥剂对生长锥的作用可能会揭示促进成人中枢神经系统神经再生的新选择。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The TC10-Exo70 complex is essential for membrane expansion and axonal specification in developing neurons.

DOI：
10.1523/jneurosci.3907-09.2009
发表时间：
2009-10-21
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Dupraz S;Grassi D;Bernis ME;Sosa L;Bisbal M;Gastaldi L;Jausoro I;Cáceres A;Pfenninger KH;Quiroga S
通讯作者：
Quiroga S

Functional analysis of SIRPalpha in the growth cone.

SIRPalpha 在生长锥中的功能分析。