高糖对脊髓损伤修复的影响及糖尿病合并脊髓损伤治疗的研究

Spinal cord injury (SCI) is the serious injuries of central nervous system. It has been demonstrated that diabetes exacerbated SCI pathological process in animal experiments and clinical trials. Managing glucose level appeared to reduce the adverse effects of diabetes on SCI recovery. With the dramatic increase in patient population of SCI with diabetes, it is imperative to examine how diabetes impact SCI and to investigate the underlying mechanisms. We have previously shown that diabetes aggravated SCI-induced rupture of blood-spinal cord barrier (BSCB) and accelerated neuronal apoptosis. However, the effect and regulatory mechanism underlying diabetes on the recovery of SCI is still poorly understood, particularly the effects of diabetes on microenvironment after SCI. In present project, we will build diabetic SCI rat models and primary cell models using high glucose to culture neurons from spinal cord. We will then investigate, both in vivo and in vitro, the molecular mechanism underlying the effect of hyperglycemia on glial scar formation, remyelination, neuron apoptosis and axonal regeneration after SCI. We will use molecular biology and histopathology methods to comprehensively evaluate the effect of hyperglycemia on microenvironment of spinal cord with or without injury. Additionally, we will further explore whether: 1) fibroblast growth factor 1(FGF1), with both the neuroprotective and antidiabetics function, can effectively treat diabetic SCI; and 2) the FGF1 level in serum can be used to predict the prognosis of diabetic SCI. Our research aims to discover new mechanisms and strategies for treating SCI patients with diabetes mellitus.

脊髓损伤（SCI）是中枢神经系统的严重创伤。目前，糖尿病(DM)合并SCI患者日益增加。动物和临床实验已证实糖尿病加重SCI病理生理进程，控制血糖水平有利于减少高糖对SCI修复的不利影响。我们前期研究也表明DM加重SCI后血脊屏障的破坏进而加速神经元凋亡。然而高糖对SCI的影响及分子机制仍不清楚，尤其是对脊髓微环境的影响尚无报道。本项目将制备糖尿病SCI大鼠模型，高糖培养原代神经元和胶质细胞模型，在体内外实验中阐明高糖对SCI后胶质瘢痕形成、再髓鞘化、神经元凋亡和轴突再生等的调控机理，通过分子生物学、组织病理学等方法评价高糖对脊髓微环境的影响；并探讨同时有神经保护和降血糖效应的药物（成纤维细胞生长因子1, FGF1）是否能有效治疗糖尿病SCI；是否能利用糖尿病SCI动物血清FGF1水平来判断预后情况。本项目将阐明糖尿病调控SCI修复的机理，为临床治疗糖尿病SCI提供理论依据和新的策略。

脊髓损伤(spinal cord injury, SCI) 是各种外伤导致的中枢神经系统严重创伤，常常使病人的运动、感觉功能以及自主支配能力丧失，给个人、家庭和社会造成巨大负担。以往研究证实糖尿病加重SCI的病理进程，阻碍运动功能恢复。目前，临床上对于SCI的治疗手段十分有限且疗效不确切，而糖尿病复杂的病理因素，使临床上治疗糖尿病合并SCI更为困难。因此，深入探究糖尿病对SCI修复的调控机制对临床上精准诊疗糖尿病合并SCI具有重要意义。本课题研究中，我们构建了糖尿病合并SCI大鼠/小鼠模型，探究糖尿病对SCI后大鼠/小鼠神经功能修复的影响。我们发现糖尿病不利于SCI后神经功能的修复。糖尿病可抑制SCI后胶质瘢痕形成，促进损伤脊髓组织中炎症状态持续加重，进而诱导神经元凋亡，增强髓鞘相关抑制因子作用，抑制轴突再生和再髓鞘化，从而加重SCI病理进程。胰岛素通过调控血糖，可保护损伤脊髓周围微环境，促进SCI后神经再生和功能修复。进一步在体内外实验研究中发现SCI早期糖尿病也会促进脊髓组织中小胶质细胞的焦亡，从而不利于小胶质细胞吞噬髓鞘碎片。本课题研究结果揭示糖尿病对SCI修复的影响及调控机制，为临床上治疗糖尿病合并SCI提供更为全面的理论依据。