Epigenetic Prevention of Diabetic Neuropathy by Vitamin C

描述(申请人提供)：糖尿病周围神经病变(DPN)是糖尿病的主要并发症和发病率和死亡率的原因。尽管付出了很多努力和投资，但这种疾病背后的致病机制尚不清楚，治疗选择仅限于疼痛管理和对症治疗。我们建议测试一种表观遗传机制，这将为新的治疗方案打开大门。研究表明，糖尿病组织中的酸性(维生素C)缺乏，是由酸性氧化为脱氢抗坏血酸(DHA)引起的。然后，DHA在细胞摄取方面被高糖击败(约1：300)，导致细胞内酸性物质减少。有趣的是，在体外雪旺细胞的轴突髓鞘形成过程中，酸性是必不可少的。已知的酸缺乏症还会导致人类周围神经病变和小鼠髓鞘减少。这是合理的，缺乏酸性在脱髓鞘的DPN起关键作用。最近，我们发现了一种新的调节DNA去甲基化的功能，这一功能已被其他人证实。抗坏血酸促进5-甲基胞嘧啶(5mC)转化为5-羟甲基胞嘧啶(5hmC)，这是DNA去甲基化的主要途径。从表观遗传学研究中获得的新见解使我们提出了一个非常规的、异常新颖的假说：雪旺细胞的表观基因组受到细胞内抗坏血酸缺乏的特异性损害，导致DPN脱髓鞘。我们设计了三个特定的目标来验证我们的假设：(1)测试抗坏血酸缺乏是否会导致体内DPN脱髓鞘；(2)测试抗坏血酸治疗是否可以延缓或防止小鼠DPN的脱髓鞘。(3)检测抗坏血酸缺乏引起的雪旺细胞表观基因组受损是否为脱髓鞘DPN的基础。验证这一假说将在以下方面对科学和健康产生重大影响。(1)明确了DPN发病的新机制，为认识DPN的发病机制提供了一个新的起点。(2)现有糖尿病啮齿动物模型均未出现脱髓鞘DPN。我们的研究将建立一个具有脱髓鞘表型的啮齿动物模型，这将对研究DPN的发病机制和筛选候选药物非常有用。(3)本研究将对糖尿病患者的临床护理产生巨大的潜在影响。在啮齿动物模型中成功地预防脱髓鞘DPN将牵涉到抗坏血酸途径来延迟或预防糖尿病患者的DPN。(4)这项研究将是研究其他糖尿病并发症，如视网膜病变和肾病的蓝图。通过使用创新的方法检验这一异常的非常规假设，本研究将加速对DPN的认识。我们独特的方法有可能为近十年来进展相对较小的领域开辟全新的道路，特别是在翻译应用方面。

DESCRIPTION (provided by applicant): Diabetic peripheral neuropathy (DPN) is a major complication and cause for morbidity and mortality in diabetes mellitus. Despite much effort and investment, there is no clear pathogenic mechanism underlying the disease and therapeutic options are limited to pain management and symptomatic treatments. We propose to test an epigenetic mechanism that will open the door to new treatment options. Studies indicate acerbate (vitamin C) deficiency in tissues of diabetes, caused by the oxidation of acerbate to dehydroascorbic acid (DHA). DHA is then outcompeted (~1:300) by high glucose for cellular uptake leading to intracellular acerbate reduction. Intriguingly, acerbate is essential in axonal myelination by Schwann cells in vitro. Acerbate deficiency also is known to cause peripheral neuropathy in humans and hypomyelination in mice. It is plausible that deficiency in acerbate plays a critical role in demyelinating DPN. Recently, we uncovered a novel function of acerbate in regulating DNA demethylation, which has been validated by others. Ascorbate enhances the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is the major pathway for active DNA demethylation. New insights gleaned from the epigenetic studies led us to develop an unconventional, exceptionally novel hypothesis: The epigenome of Schwann cells is impaired specifically by intracellular ascorbate shortage, leading to demyelinating DPN. Three specific aims are designed to test our hypothesis: (1) To test whether ascorbate deficiency causes demyelinating DPN in vivo; (2) To test whether ascorbate treatment can delay or prevent demyelinating DPN in mice. (3) To test whether an impaired epigenome of Schwann cells caused by ascorbate deficiency underlies demyelinating DPN. Testing this hypothesis will have a significant impact on science and health in the following aspects. (1) Identifying a novel mechanism for DPN and a fresh start for this field to understand pathomechanisms. (2) None of the current rodent models of diabetes mellitus develop demyelinating DPN. Our research will establish a rodent model with demyelination phenotypes, which will be extremely useful to study DPN pathogenesis and to screen drug candidates. (3) This research will have a huge potential impact on clinical care of diabetic patients. Successful prevention of demyelinating DPN in rodent models will implicate the ascorbate pathway to delay or prevent DPN in diabetic patients. (4) This study will be a blueprint for investigations into other diabetic complications such as retinopathy and nephropathy. By testing the exceptionally unconventional hypothesis using innovative approaches, this research will accelerate the knowledge of DPN. Our unique approach has the potential to open up entirely new pathways to a field that has made relatively little progress in the recent decade, especially in terms of translational applications.