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Transduction Mechanisms Mediating Nerve Growth Cone Guidance

介导神经生长锥引导的转导机制

基本信息

批准号：
8730718
负责人：
John Richard Henley
金额：
$ 33.47万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730718
关键词：
Address Adhesions Axon Biological Assay Biological Models Biosensor Brain-Derived Neurotrophic Factor Cell membrane Cell physiology Cells Chemotactic Factors Chemotaxis Chimeric Proteins Complex Cues DNA Sequence Rearrangement Detection Dominant-Negative Mutation Dyes Dynamin ECM receptor Endocytosis Exocytosis Extracellular Matrix Feedback Goals Growth Cones Image Immunoassay In Vitro Injury Integrins Label Life Link Mediating Membrane Methods Microscopic Modeling Molecular Myelin Myelin Associated Glycoprotein Natural regeneration Nerve Nervous System Trauma Nervous system structure Neurodegenerative Disorders Neurons Oligonucleotides Phosphatidylinositols Phosphotransferases Process Proteins Receptor Activation Recovery of Function Recycling Regulation Research Role Signal Transduction Signal Transduction Pathway Spinal Surface Therapeutic Total Internal Reflection Fluorescent Vesicle Xenopus axon growth axon guidance base cell growth regulation cellular imaging extracellular fluorescence imaging human NTN1 protein in vivo insight mutant nervous system development netrin-1 novel phosphatidylinositol 3,4,5-triphosphate prevent receptor release factor trafficking

项目摘要

DESCRIPTION (provided by applicant): The growth cone of developing axons guides axon extension through the extracellular matrix (ECM) by sensing gradients of environmental guidance cues that initiate attractive or repulsive steering. Chemotactic growth cone guidance is also important in the context of nervous system injury, as factors released from the breakdown of myelin may act as chemorepellents and inhibit axon elongation, thereby preventing functional recovery. Understanding the molecular mechanisms that mediate growth cone guidance could provide important insights for developing strategies to enhance regeneration after injury or neurodegenerative disease. Cytoplasmic Ca2+ signals mediate the action of many guidance cues, but the link between surface receptor activation and Ca2+ signaling is largely unknown. Likewise, an understanding of the cellular processes underlying growth cone chemotaxis remains incomplete. Current models rely heavily on cytoskeletal rearrangements, but in vivo studies have demonstrated that regulated adhesion to the ECM is also critical for proper guidance. The goal of the proposed research is to define the transduction mechanisms underlying the chemotactic guidance of axonal growth cones. Specifically, we aim to define the intracellular signals that mediate growth cone detection of extracellular guidance cues, the interactions between early signal transduction pathways, and the regulation of downstream effector processes that control the direction of axon extension. Our preliminary findings have led us to establish a CENTRAL HYPOTHESIS that growth cone detection of guidance cues is mediated by polarized phosphoinositide 3-kinase (PI3K) and Akt signaling at the surface membrane, which triggers local Ca2+ signals and stimulates endocytic and exocytic machinery to redistribute receptors for ECM and guidance cues asymmetrically at the growth cone surface and initiate chemotactic guidance. The proposal is organized into four interrelated specific aims that will define the following: first, the role of PI3K/Akt signaling in mediating growth cone chemotaxis; second, how PI3K/Akt signaling activates Ca2+ guidance signals in the growth cone; third, how PI3K/Akt and Ca2+ signaling regulate vesicle dynamics during growth cone turning; and fourth, how PI3K/Akt and Ca2+ signaling regulate trafficking of integrin and guidance receptors during growth cone turning. This study will provide novel insights into the early signals that mediate the detection of guidance cues, the amplification of guidance signals, and the regulation of cellular machinery that controls membrane dynamics and the redistribution of surface receptors during chemotactic growth cone guidance.

描述（由申请人提供）：发育中的轴突的生长锥通过感知环境引导信号的梯度来引导轴突通过细胞外基质（ECM）伸展，从而启动吸引或排斥转向。趋化生长锥引导在神经系统损伤的情况下也很重要，因为髓磷脂分解释放的因子可能起到趋化补剂的作用，抑制轴突伸长，从而阻止功能恢复。了解介导生长锥引导的分子机制可以为制定增强损伤或神经退行性疾病后再生的策略提供重要见解。细胞质Ca2+信号介导许多引导信号的作用，但表面受体激活和Ca2+信号之间的联系在很大程度上是未知的。同样，对生长锥趋化性的细胞过程的理解仍然不完整。目前的模型严重依赖于细胞骨架重排，但体内研究表明，对ECM的粘附调节也是正确引导的关键。本研究的目的是确定轴突生长锥的趋化引导的转导机制。具体来说，我们的目标是定义介导生长锥检测细胞外引导信号的细胞内信号，早期信号转导途径之间的相互作用，以及控制轴突延伸方向的下游效应过程的调节。我们的初步研究结果使我们建立了一个中心假设，即生长锥对引导信号的检测是由表面膜上的极化磷酸肌肽3-激酶（PI3K）和Akt信号介导的，这些信号触发局部Ca2+信号，刺激内噬和胞外机制，使ECM和引导信号的受体在生长锥表面不对称地重新分配，并启动趋化引导。该提案分为四个相互关联的具体目标，将定义以下内容：首先，PI3K/Akt信号在介导生长锥趋化性中的作用；二是PI3K/Akt信号如何激活生长锥内Ca2+引导信号；第三，PI3K/Akt和Ca2+信号如何调节生长锥转向过程中的囊泡动力学；第四，PI3K/Akt和Ca2+信号如何调节生长锥转向过程中整合素和引导受体的运输。该研究将为在趋化生长锥引导过程中介导引导信号的检测、引导信号的放大以及控制膜动力学和表面受体重新分配的细胞机制的调节提供新的见解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Asymmetric endocytosis and remodeling of beta1-integrin adhesions during growth cone chemorepulsion by MAG.

DOI：
10.1038/nn.2554
发表时间：
2010-07
期刊：
NATURE NEUROSCIENCE
影响因子：
25
作者：
Hines, Jacob H.;Abu-Rub, Mohammad;Henley, John R.
通讯作者：
Henley, John R.

Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth.

DOI：
10.1186/1741-7007-9-82
发表时间：
2011-11-30
期刊：
BMC biology
影响因子：
5.4
作者：
Carlstrom LP;Hines JH;Henle SJ;Henley JR
通讯作者：
Henley JR

Asymmetric PI(3,4,5)P3 and Akt signaling mediates chemotaxis of axonal growth cones.

DOI：
10.1523/jneurosci.0216-11.2011
发表时间：
2011-05-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Henle SJ;Wang G;Liang E;Wu M;Poo MM;Henley JR
通讯作者：
Henley JR