腓骨肌萎缩症中遗传与环境因素互作的分子机制及潜在治疗方案

Emerging evidence has begun to reveal that neurological diseases may arise from a combination of genetic risk factors and environmental influences. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies that are characterized by progressive motor/sensory dysfunction. A subtype of the diseases—CMT2D—is caused by dominant mutations in GARS gene, encoding the ubiquitously expressed enzyme glycyl-tRNA synthetase (GlyRS). The PI’s recent studies have revealed that CMT2D mutations alter the conformation of GlyRS, enabling mutant GlyRS to bind Nrp1. This aberrant interaction antagonizes the binding of vascular endothelial growth factor (VEGF) to Nrp1, thereby contributing to motor defects in CMT2D. These findings link the CMT2D pathology to the neomorphic binding activity of mutant GlyRS that antagonizes the VEGF/Nrp1 interaction. However, in many cases, CMT patients carry the same gene mutation but may develop substantial clinical variability in disease expression. Recent clinical studies have revealed that environmental factors such as vitamin D deficiency predispose to the development of peripheral neuropathy symptoms. However it remains unclear whether these genetic and environmental pathways are integrated into a hierarchical signaling network that contributes to peripheral nerve pathology. The overall goal of this proposal is to characterize the signal integration of Vitamin D and GARS pathways in CMT2D pathogenesis. The proposed experiments are expected to reveal the key molecular link that integrates genetic and environmental factors in CMT2D, and to identify the actionable targets for treating CMT2D.

大部分的神经系统疾病都是由遗传因素和环境因素共同作用的结果。腓骨肌萎缩症（Charcot-Marie-Tooth Neuropathy，CMT）是最常见的遗传性周围神经系统疾病之一，其中CMT2D亚型是由GARS基因上的显性遗传突变所引起的，该基因编码甘氨酰-tRNA合成酶。本项目的前期研究发现：GARS基因上的致病突变会导致其蛋白质构象发生改变,使得突变蛋白获得异常的结合活性，干扰VEGF/Nrp1信号通路，从而导致运动神经病变。事实上，临床上有大量的CMT病例，患者携带相同的基因突变, 却在临床症状的严重程度上表现出很大的差异性。大量证据表明维生素D缺乏等环境因素很可能在这个过程中扮演了重要角色。本项研究将以CMT2D为切入点，针对维生素D介导的环境因素和GARS基因突变所介导的遗传因素之间的分子联系和信号整合展开研究，并探索维生素D信号通路作为治疗CMT药物靶点的潜力。

CMT是最常见的周围神经遗传病，其中CMT2D亚型是一种轴突型的CMT。CMT2D主要导致运动轴突退变以及运动功能障碍。我们以前的研究表明，CMT2D致病突变会导致GlyRS蛋白构象发生改变，使其异常结合Nrp1受体，破坏VEGF/Nrp1信号通路。虽然针对遗传通路的研究非常重要，越来越多的研究表明环境因素在复杂疾病的发病过程中也扮演了非常重要的角色。然而，CMT发病过程中的环境通路并不清楚。在本项目中，我们使用了小鼠遗传学、行为学、药理学、分子生化等多种技术手段，揭示了维生素D是影响CMT2D疾病进程的重要环境因子。我们发现：（1）维生素D摄入不足会导致CMT2D小鼠的疾病表型进一步恶化；（2）维生素D信号通路可以调节VEGF的表达；（3）利用维生素D衍生药物上调VEGF的表达可以有效改善CMT2D小鼠的疾病表型。本研究提示维生素D衍生药物具有治疗CMT的潜力，揭示了VEGF是介导CMT2D遗传通路与环境通路互作的重要分子联系。

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