Growth Cone Adhesion And Motility

轴突的生长尖端，神经生长锥通过变形运动前进，这一过程涉及 协调调节肌动蛋白细胞骨架和细胞粘附。生长锥附着力不好 理解，但最近的数据表明，淀粉样前体蛋白（APP）是丰富的生长锥， 与它们的粘连有关。本项目将检验APP参与调控的假设 的整合素介导的生长锥粘附，APP影响生长锥运动在体外和体内。 具体的目的是通过以下几个方面来检验这些假设：（1）分析生长锥的扩展和粘附， APP和整合素功能获得和丧失的体外条件;和（2）研究轴突生长和 在体内发芽，在突变小鼠中错误表达APP。这些目标将与细胞组合 成像、分子和生物化学方法以及基因工程小鼠模型。 这些研究有望为生长锥的粘附机制提供新的数据， 因此，对于我们理解轴突生长和发育中的寻路是重要的。此外，委员会认为， 研究结果有望深入了解APP迄今为止鲜为人知的功能，特别是在 神经系统发育由于APP在唐氏综合征中过度表达，预期的数据可能会 为唐氏综合症儿童认知缺陷的可能原因提供了新的见解，他们还将 影响了我们对阿尔茨海默病致病过程的理解。

The axon's growing tip, the nerve growth cone advances by amoeboid locomotion, a process that involves concerted regulation of the actin cytoskeleton and cell adhesion. Growth cone adhesion is not well understood, but recent data indicate that amyloid precursor protein (APP) is enriched in growth cones and associated with their adhesions. This project will test the hypotheses that APP is involved in the regulation of integrin-mediated growth cone adhesion, and that APP affects growth cone motility in vitro and in vivo. The specific aims are to test these hypotheses by: (1) analyzing growth cone spreading and adhesion in conditions of APP and integrin gain and loss of function in vitro; and (2) studying axonal growth and sprouting in vivo, in mutant mice mis-expressing APP. These aims will be pursued with a combination of cell imaging, molecular and biochemical approaches as well as genetically engineered mouse models. The proposed studies are expected to provide new data on the growth cone's adhesion mechanism and, thus, are important for our understanding of axonal growth and pathfinding in development. Furthermore, results are expected to yield insights into the so far little understood function of APP, especially during nervous system development. As APP is over-expressed in Down syndrome, the expected data are likely to provide new insights into possible causes of cognitive deficits in Down syndrome children, and they also will impact our understanding of pathogenic processes in Alzheimer's disease.