The role of cGMP-GKI signalling in spinal cord axonal sprouting and regeneration following injury

cGMP-GKI信号在损伤后脊髓轴突萌芽和再生中的作用

基本信息

批准号：
187629742
负责人：
Professor Dr. Simone Di Giovanni
金额：
--
依托单位：
Department of Medicine
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/187629742?language=en
关键词：
role cGMP GKI signalling spinal

项目摘要

Spinal cord injury leads to long term neurological impairment that largely depends upon the incapacity of lesioned spinal axons to sprout and regenerate and to re-establish appropriate synaptic contacts1-3. The limited or absent regenerative ability of injured axons is primarily due to the collapse of their growth cones. The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts growth cone collapse induced by Semaphorin 3A (Sema3A), which also limits regeneration following spinal injuries4. We have recently shown that neuronal cGKI expression is directly regulated by the transcription factor p53, which is required for physiological axonal regeneration5,6. However, a role for cGMP-GKI pathways in p53 dependent and independent axonal outgrowth and regeneration following spinal injuries remains elusive. We hypothesize that cGMP-GKI cascade is essential for physiological axonal sprouting and for axonal regeneration and that cGMP-GKI gain of function experiments would lead to enhanced axonal sprouting and regeneration following spinal injury, including in mice lacking neuronal p53. We will employ a spinal dorsal overhemisection at T8 in mice to specifically investigate (1) axonal regeneration and sprouting as well as functional recovery in mice lacking cGKI in nestin positive neurons (cGKI nestin -/-) and (2) the capacity of enhanced cGMP-cGKI signaling (via pharmacological means and viral cGKI delivery) to promote axonal sprouting and regeneration in wild type as well as in p53 loxP/nestin cre mice.Ultimately, this study may provide novel molecular and pharmacological tools to enhance axonal regeneration following spinal lesions and may clarify the cGMP-cGKI as well as the p53-dependent pro-regeneration pathways.

脊髓损伤导致长期神经系统损伤，很大程度上取决于病变的脊柱轴突的丧失能力来发芽和再生并重新建立适当的突触接触1-3。受伤的轴突的有限或不具有再生能力主要是由于其生长锥的崩溃。 CGMP依赖性蛋白激酶I型（CGKI）具有多个功能，包括在轴突生长和感觉神经元的途径中的作用，并抵消Semaphorin 3A（SEMA3A）诱导的生长锥塌陷，这也限制了脊髓损伤后再生的限制。我们最近表明，神经元CGKI表达受到转录因子p53的直接调节，这是生理轴突再生所需的5,6。但是，脊柱损伤后CGMP-GKI途径在p53依赖和独立的轴突生长和再生中的作用仍然难以捉摸。我们假设CGMP-GKI级联对于生理轴突发芽和轴突再生至关重要，并且CGMP-GKI功能实验的增益将导致轴突发芽和脊柱损伤后的轴突芽和再生增强，包括缺乏神经元P53缺乏神经元P53的小鼠。我们将在小鼠T8处采用脊柱背层过度测量，以特别研究（1）轴突再生和发芽以及在Nestin阳性神经元（CGKI NESTIN - / - ）中缺乏CGKI的小鼠中的轴突再生以及功能恢复，并通过增强的CGMP-CGKISIDAL和VIRAL ADRAVINAL SPARTAL SAVERAL PRACHITAL和VIRAL SAVINAL SAVINAL SAVERINAL和VIRAL SAVINEL的能力（类型以及p53 Loxp/Nestin Cre小鼠。本文可能提供新型的分子和药理工具，以增强脊柱病变后的轴突再生，并可以阐明CGMP-CGKI以及p53依赖性的促促培养发途径。