Epigenetic Prevention of Diabetic Neuropathy by Vitamin C

维生素 C 对糖尿病神经病变的表观遗传学预防

• 批准号: 8932611
• 负责人: Gaofeng Wang
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932611
• 关键词: Affect; American; Ascorbic Acid; Ascorbic Acid Deficiency; Behavioral; Biochemistry; Cells; Complication; Complications of Diabetes Mellitus; DNA; Dehydroascorbic Acid; Demyelinations; Diabetes Mellitus; Diabetic Neuropathies; Disease; Epigenetic Process; Gene Expression Profile; Genome; Glean; Glucose; Grant; Gulo; Health Sciences; Human; Hyperglycemia; In Vitro; Injection of therapeutic agent; Investigation; Investments; Journals; Kidney Diseases; Knowledge; Lead; Liver; Morbidity - disease rate; Mus; Nerve; Pain management; Paper; Pathogenesis; Pathway interactions; Peripheral Nervous System Diseases; Phenotype; Play; Prevention; Process; Publishing; Research; Research Personnel; Retinal Diseases; Risk; Rodent Model; Role; Schwann Cells; Streptozocin; Testing; Therapeutic; Tissues; ascorbate; base; clinical care; cost; deep sequencing; demethylation; design; diabetic; diabetic patient; dietary supplements; drug candidate; effective therapy; epigenome; experience; glycemic control; hereditary neuropathy; in vivo; innovation; insight; mortality; myelination; novel; novel therapeutics; oxidation; prevent; public health relevance; research study; social; success; uptake

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.

描述（由申请人提供）：糖尿病周围神经病变（DPN）是糖尿病发病率和死亡率的主要并发症和原因。尽管付出了巨大的努力和投入，但仍没有明确的致病机制，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，糖尿病组织中的酸盐（维生素C）缺乏，是由酸盐氧化为脱氢抗坏血酸（DHA）引起的。DHA随后被高葡萄糖取代（约1:300），用于细胞摄取，导致细胞内酸还原。有趣的是，在体外雪旺细胞轴突髓鞘形成过程中，酸是必不可少的。已知急性缺乏症也会引起人类周围神经病变和小鼠髓鞘发育低下。这似乎是合理的，缺乏在脱髓鞘DPN起关键作用。最近，我们发现了一种新的酸盐在调节DNA去甲基化中的功能，这已经被其他人证实了。抗坏血酸促进5-甲基胞嘧啶（5mC）向5-羟甲基胞嘧啶（5hmC）的转化，这是活性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，非常新颖的假设：雪旺细胞的表观基因组受到细胞内抗坏血酸缺乏的损害，导致DPN脱髓鞘。为了验证我们的假设，我们设计了三个具体目标：(1)在体内测试抗坏血酸缺乏是否会导致DPN脱髓鞘；(2)检验抗坏血酸治疗是否能延缓或预防小鼠DPN脱髓鞘。(3)检验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性DPN的基础。验证这一假设将在以下方面对科学和健康产生重大影响。(1)确定DPN的新机制，为该领域理解病理机制提供了新的起点。(2)目前的糖尿病啮齿动物模型均未发生脱髓鞘性DPN。我们的研究将建立具有脱髓鞘表型的啮齿动物模型，这对研究DPN的发病机制和筛选候选药物具有重要意义。(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。在啮齿类动物模型中成功预防脱髓鞘性DPN将涉及抗坏血酸途径延迟或预防糖尿病患者的DPN。(4)本研究将为其他糖尿病并发症如视网膜病变和肾病的研究提供蓝本。通过使用创新方法测试非常规假设，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少的领域开辟全新的途径，特别是在转化应用方面。