维生素D3及其代谢酶CYP24A1对糖代谢的调控及在糖尿病周围神经病变中的保护作用研究

维生素D3缺乏与糖尿病周围神经病变患病风险密切相关，但机制不明。雪旺细胞是周围神经唯一支持细胞，我们前期研究高糖对雪旺细胞的影响时发现，高糖引起维生素D3代谢酶CYP24A1基因及蛋白增加。CYP24A1具有代谢失活维生素D3活性产物的1,25（OH）2D3的能力，并在1,25（OH）2D3刺激后可明显升高。我们将CYP24A1在雪旺细胞中过表达或沉默之后，发现细胞内葡萄糖水平发生显著变化，那么CYP24A1引起雪旺细胞糖代谢改变，很可能是维生素D3对糖尿病周围神经病变影响的重要因素。本课题通过构建CYP24A1基因条件性敲除转基因糖尿病小鼠模型，从动物行为神经功能检测，体外神经纤维病理学检查及细胞分子生物学层面深入研究，探索CYP24A1影响葡萄糖代谢的分子机制及对糖尿病周围神经病变的影响，并进一步明确维生素D3与糖尿病周围神经病变的关系，为糖尿病周围神经病变治疗寻找新的治疗靶点。

Vitamin D3 deficiency is closely associated with diabetic peripheral neuropathy risk, but the mechanism is not clear. Schwann cells are the only peripheral nerve supporting cells. When we study the effects of high glucose on Schwann cells, found that high glucose caused vitamin D3 metabolic enzyme CYP24A1 gene and protein increasing. CYP24A1 can inactivate 1,25 (OH) 2D3 that is a product of vitamin D3, and can be significantly increased after 1,25 (OH) 2D3 stimulation. We found that intracellular glucose levels changed significantly after CYP24A1 overexpressing or silencing in Schwann cells.We hypothesis that it is a important factor for effect of vitamin D3 on diabetic peripheral neuropathy that CYP24A1 causes Schwann cells glucose metabolism to change. Constructing CYP24A1 gene conditional knockout transgenic mouse model of diabetes, from animal behavior neurological testing, in vitro cellular and molecular biology and nerve fibers pathology to explore the molecular mechanisms of the CYP24A1 affecting glucose metabolism and impacting diabetic peripheral neuropathy . Further to clarify vitamin D3 and diabetic peripheral neuropathy relations in order to find new therapeutic targets for the treatment of diabetic peripheral neuropathy .