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.

脊髓损伤会导致长期的神经损伤，这在很大程度上取决于受损的脊髓轴突无法发芽和再生以及重新建立适当的突触接触1-3。受伤轴突再生能力有限或缺失主要是由于其生长锥的塌陷。 cGMP 依赖性蛋白激酶 I 型 (cGKI) 具有多种功能，包括在轴突生长和感觉神经元寻路中发挥作用，并抵消信号蛋白 3A (Sema3A) 诱导的生长锥塌陷，这也限制了脊髓损伤后的再生4。我们最近表明，神经元 cGKI 表达直接受转录因子 p53 调节，这是生理轴突再生所必需的 5,6。然而，cGMP-GKI 通路在脊髓损伤后 p53 依赖性和独立性轴突生长和再生中的作用仍然难以捉摸。我们假设 cGMP-GKI 级联对于生理轴突萌芽和轴突再生至关重要，并且 cGMP-GKI 功能获得实验将导致脊髓损伤后轴突萌芽和再生增强，包括在缺乏神经元 p53 的小鼠中。我们将在小鼠 T8 处采用脊髓背侧半切术来专门研究 (1) 巢蛋白阳性神经元 (cGKI 巢蛋白 -/-) 中缺乏 cGKI 的小鼠的轴突再生和发芽以及功能恢复和 (2) 增强的 cGMP 的能力-cGKI 信号传导（通过药理学手段和病毒 cGKI 传递）促进野生型以及 p53 loxP/nestin cre 中的轴突萌芽和再生最终，这项研究可能提供新的分子和药理学工具来增强脊髓损伤后的轴突再生，并可能阐明 cGMP-cGKI 以及 p53 依赖性促再生途径。