Growth Cone Adhesion And Motility

生长锥粘附和运动

基本信息

批准号：
7783130
负责人：
KARL H PFENNINGER
金额：
$ 36.59万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7783130
关键词：
Actins Adhesions Adhesives Adult Affect Alzheimer&apos s Disease Amyloid beta-Protein Precursor Axon Binding Biochemical Brain Cell Adhesion Cell Adhesion Molecules Child Cognitive Cognitive deficits Cues Cytoskeleton Data Development Disease Down Syndrome Environment Extracellular Matrix Genetically Engineered Mouse Glycoproteins Goals Growth Cones Hippocampus (Brain)In Vitro Individual Injury Integrins Knockout Mice Knowledge Laboratories Laminin Ligands Locomotion MARCKS gene Mediating Molecular Mutant Strains Mice Natural regeneration Nerve Nerve Fibers Neurites Neurons Pathogenesis Peptides Phenotype Phosphotransferases Play Presenile Alzheimer Dementia Process Proteins Regulation Research Role Structure Testing amyloid precursor protein ligand axon growth axonal sprouting cell motility cellular imaging disability in vivo insight interest loss of function mouse development mouse model nerve supply nervous system development overexpression

项目摘要

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.

轴突不断增长的尖端，神经生长锥通过变形自动运动前进，该过程涉及肌动蛋白细胞骨架和细胞粘附的协同调节。生长锥粘附不好理解，但最近的数据表明，淀粉样蛋白前体蛋白（APP）富含生长锥和与它们的粘连相关。该项目将测试应用程序参与法规的假设整联蛋白介导的生长锥粘附，该应用在体外和体内影响生长锥运动。具体目的是通过：（1）分析生长锥扩散和粘附 APP和整联蛋白增益的条件和体外功能的丧失；（2）研究轴突生长和在体内发芽，在突变小鼠中表达的应用程序。这些目标将与细胞结合在一起成像，分子和生化方法以及基因工程的小鼠模型。拟议的研究预计将提供有关生长锥的粘附机制的新数据，并提供因此，对于我们对轴突生长和发育中的探路很重要。此外，期望结果能够对迄今为止应用程序的功能产生见解，尤其是在神经系统的发展。由于应用程序在唐氏综合症中过度表达，因此预期数据可能会提供有关唐氏综合症儿童认知缺陷可能原因的新见解，他们也会影响我们对阿尔茨海默氏病的致病过程的理解。