转录因子Nfia在慢性痛与慢性痒形成中的调控作用机制研究

The ability of somatic sensory neurons in dorsal root ganglion (DRG) to discriminate diverse types of peripheral stimuli is reflected by the high heterogeneity of neuronal subtypes. To understand how this cell diversity is generated during development remains a challenge. Furthermore, the functional changes of these neurons in neuropathic or inflammatory conditions constitute important mechanisms underlying the development of chronic pain and chronic itch, while the management of chronic pain and chronic itch is frequently unsatisfactory. Thus, the development of specific and efficient therapies requires better understanding of the neuronal properties of sensory neurons, and the regulatory mechanisms of their development and functions in normal and pathological conditions. Our preliminary data showed that removal of the transcription factor Nuclear Factor I/A (Nfia) in DRG eliminated the expression of itch neuron markers, NPPB and IL31ra, which consequently leaded to substantial reductions of scratching elicited by pruritogen-injection or in chronic itch model. More interestingly, Nfia conditional knockout (cKO) mice showed specific dynamic allodynia defect in chronic constriction injury (CCI) model, whilst static allodynia remained intact, suggesting different pathways/mechanisms involved in the development of dynamic and static allodynia, respectively. In this project, the Nfia cKO mice will be used to study the function of Nfia in the development of sensory neurons, and its regulatory role in the development of chronic pain and chronic itch. These results will be of great significance in discovering the specific pathway/mechanisms of dynamic allodynia, and will provide important basis and intriguing implications for the design of more effective therapies to conquer chronic pain and chronic itch.

躯体感觉神经元具有高度多样性，其产生机理是神经生物学领域的研究热点之一。此外，这些神经元在炎症、神经损伤等条件下的特性改变是慢性痛和慢性痒的主要成因之一，而慢性痛和慢性痒的临床治疗始终是医学难题。因而要求对感觉神经元发育及其在不同条件下的功能调控机制作进一步研究。本项目申请人的前期研究结果显示：敲除转录因子Nfia导致小鼠痒神经元标记NPPB和IL31ra的表达缺失，以及急性痒和慢性痒应答的显著缺陷；更有趣的是，Nfia条件敲除小鼠在神经损伤模型中只表现出动态机械刺激诱发痛症状的缺失，静态机械刺激诱发痛症状不受影响，说明这两种慢性痛症状可能由不同通路或机制介导产生。本项目拟利用Nfia条件敲除小鼠，详细研究转录因子Nfia在DRG神经元发育中的作用及其对慢性痛和慢性痒的调控机制，并阐明介导动态机械刺激诱发痛的特异性通路。这些结果有望为慢性痒和慢性痛的临床治疗提供有益的理论支持和新的思路。

DRG神经元在炎症、神经损伤等条件下的特性改变是慢性痛和慢性痒的主要成因之一，而慢性痛和慢性痒的临床治疗始终是医学难题。因而要求对感觉神经元发育及其在不同条件下的功能调控机制作进一步研究。本项目研究结果显示：Runx1在痒感受器神经元发育过程中起到重要的调节作用，在早期胚胎发育过程中Runx1的调节对Nppb+神经元是必须的，而在发育的晚期Runx1对其中一些痒感受器神经元起到抑制作用；Nfia的表达开始于小鼠E12.5-E13.5持续到成年，敲除转录因子Nfia导致小鼠痒神经元NP3谱系的表达缺失而MrgprA3+ NP2表达上升，急性痒反应出现明显缺陷，并且在过敏源诱发慢性痒模型中的慢性痒症状消失；更有趣的是，Nfia条件敲除小鼠对一般冷痛、热痛、轻触等并无影响，在坐骨神经慢性压迫性损伤、保留性神经损伤、脊神经结扎三种神经损伤模型中只表现出动态机械刺激诱发痛症状的缺失，静态机械刺激诱发痛症状不受影响，说明这两种慢性痛症状可能由不同通路或机制介导产生。本项目利用条件敲除小鼠，详细研究转录因子Runx1和Nfia在DRG神经元发育中的作用及其对慢性痛和慢性痒的调控机制，并阐明介导动态机械刺激诱发痛的特异性通路。这些结果有望为慢性痒和慢性痛的临床治疗提供有益的理论支持和新的思路。