CRMP2 is necessary for Neurofibromatosis type 1 related pain.
CRMP2 is necessary for Neurofibromatosis type 1 related pain.
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DOI：
10.1080/19336950.2017.1370524
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Khanna R
中科院分区：
文献类型：
--
作者：
Moutal A;Cai S;Luo S;Voisin R;Khanna R
1型神经纤维瘤病（NF 1）是最常见的遗传性疾病之一，大约每3000人中就有1人患病。作为一种多系统疾病，它影响认知发育，以及骨骼，神经和肌肉的构成。NF 1周围神经病变是一种潜在的严重临床并发症，与发病率和死亡率增加相关。神经纤维瘤病1型（NF 1）疼痛的有效治疗方法的发现依赖于对机制的理解，这在一定程度上受到了NF 1疼痛相关动物模型相对缺乏的限制。我们在大鼠中使用鞘内靶向编辑Nf 1，以提供神经纤维蛋白和疼痛反应之间因果关系的直接证据。我们证明，神经纤维蛋白的编辑导致外周伤害感受器的功能重塑，其特征在于增强河豚毒素敏感性（TTX-S）Na+电压门控钠通道（NaV1.7）和降钙素反应介体蛋白2（CRMP 2）的相互作用。总的来说，这些外周适应增加感觉神经元的兴奋性和兴奋性递质向脊髓背角的释放，以建立和维持由对后爪的机械刺激的痛觉过敏所反映的中枢致敏状态。这里提供的数据表明，CRMP 2抑制足以逆转Nf 1基因编辑后观察到的电压门控离子通道和神经递质释放的失调。通过CRMP 2导向策略使离子通道失调正常化和痛觉过敏的一致性支持CRMP 2的翻译靶向以抑制NF 1相关疼痛。
Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, affecting roughly 1 in 3000 individuals. As a multisystem disorder, it affects cognitive development, as well as bone, nerve and muscle constitution. Peripheral neuropathy in NF1 constitutes a potentially severe clinical complication and is associated with increased morbidity and mortality. The discovery of effective therapies for Neurofibromatosis type 1 (NF1) pain depends on mechanistic understanding that has been limited, in part, by the relative lack of availability of animal models relevant to NF1 pain. We have used intrathecal targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin and pain responses. We demonstrated that editing of neurofibromin results in functional remodeling of peripheral nociceptors characterized by enhancement of interactions of the tetrodotoxin-sensitive (TTX-S) Na+ voltage-gated sodium channel (NaV1.7) and the collapsin response mediator protein 2 (CRMP2). Collectively, these peripheral adaptations increase sensory neuron excitability and release of excitatory transmitters to the spinal dorsal horn to establish and maintain a state of central sensitization reflected by hyperalgesia to mechanical stimulation of the hindpaw. The data presented here shows that CRMP2 inhibition is sufficient to reverse the dysregulations of voltage-gated ion channels and neurotransmitter release observed after Nf1 gene editing. The concordance in normalization of ion channel dysregulation by a CRMP2-directed strategy and of hyperalgesia supports the translational targeting of CRMP2 to curb NF1-related pain.
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影响因子：
46.9
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通讯作者：
Khanna R