Role of Complex Sphingolipids in Diabetic Neuropathy

复合鞘脂在糖尿病神经病变中的作用

• 批准号: 10624978
• 负责人: VERA FRIDMAN
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624978
• 关键词: Address; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Alanine; Amino Acids; Animal Model; Animals; Automobile Driving; Biological; Biological Markers; Biology; Biopsy; Case/Control Studies; Clinical; Clinical Research; Clinical Trials; Colorado; Complex; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Diagnosis; Disease; Endocrinology; Enzymes; Epidemiology; Ethnic Origin; Exclusion; Future; Goals; Grant; Health Services Accessibility; Hereditary Sensory and Autonomic Neuropathies; High Prevalence; Hyperglycemia; Infrastructure; Intervention; Knowledge; Lipids; Mass Spectrum Analysis; Measures; Mentorship; Metabolic; Metabolism; Michigan; Modeling; Morbid Obesity; Nerve Fibers; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outcome Measure; Pain; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Prevention strategy; Quality of life; Race; Reaction; Reporting; Research Design; Research Personnel; Rodent Model; Role; Sampling; Serine; Severities; Skin; Sphingolipids; Statistical Methods; Supplementation; Symptoms; Techniques; Testing; Therapeutic Intervention; Thinness; Time; Training; Universities; Visit; Work; Youth; blood glucose regulation; clinical outcome measures; clinical translation; clinically relevant; cohort; comparison control; density; effective therapy; improved; instrument; nerve conduction study; neurotoxic; novel; novel therapeutics; obese person; oral supplementation; professional atmosphere; programs; prospective; rare genetic disorder; recruit; screening; serine palmitoyltransferase; sex; targeted treatment; therapeutic target

PROJECT SUMMARY/ABSTRACT Diabetic neuropathy (DN) is a painful and debilitating condition that affects 50% of people with diabetes. Despite its high prevalence, the precise biological mechanisms of DN are not known and no disease arresting treatment is currently available. There is therefore a critical need for the identification of therapeutic targets and preventative strategies for DN. Recent data show that sphingolipid metabolism is altered in type 2 diabetes (T2D), resulting in the accumulation of atypical, neurotoxic deoxysphingolipids (dSLs). dSLs are known to increase in the setting of low levels of the amino acid L-serine and high levels of L-alanine, but the cause of dSL accumulation in diabetes is not known. Importantly, oral supplementation with the amino acid L-serine suppresses formation of dSLs and improves neuropathy in animal models of DN, suggesting that dSLs could play a role in DN. The proposed study aims to define the specific dSL molecules that are most closely associated with DN and evaluate the contribution of altered L-alanine to L-serine ratios to dSL accumulation in T2D. Defining the specific molecules in the dSL pathway that are most closely associated with DN and understanding the cause for their formation could lead to the development of targeted therapeutic interventions for the disease. Advanced mass spectrometry techniques have been used to demonstrate elevations in select dSLs (1- deoxydihyroceramides) in a small cohort of adults with morbid obesity, T2D and DN. Results showed that 1) L- serine levels were lower and L-alanine levels higher in subjects with DN as compared to controls; and 2) that increased L-alanine to L-serine ratios correlated positively with dSLs and with DN severity. In Aim 1 of the proposed studies, the same state of the art techniques will be used to examine detailed dSL profiles and amino acid levels cross-sectionally and longitudinally in the Treatment Options for T2D in Adolescents and Youth (TODAY) cohort. These studies will examine whether L-alanine to L-serine ratios are associated with dSL accumulation in youth onset T2D in a cross sectional comparison (Aim 1a); and test whether elevations in L-alanine to L-serine ratios and dSLs are associated with an increased odds of developing DN using a retrospective case-control study design (Aim 1b). In Aim 2, correlations between dSLs and L-alanine to L-serine ratios to DN severity will be examined in an adult T2D cohort (without the confounder of morbid obesity) at the University of Colorado using validated DN measures including nerve fiber density on skin biopsy. The K23 grant will allow the candidate to pursue training in 1) clinical outcome measures specific to DN, 2) epidemiologic principles and statistical methods, and 3) fundamentals of lipid biology and mass spectrometry. The mentorship and advising of Drs. Jane Reusch, Robert Murphy, Bryan Bergman, Eva Feldman, and Leslie Lange, whose expertise spans endocrinology, DN, epidemiology and lipid biology, is ideally suited for this project. The University of Colorado Denver offers the optimal environment for this work, with a leading clinical research program in T2D, and extensive infrastructure for supporting junior investigators.

项目概要/摘要 糖尿病神经病变 (DN) 是一种痛苦且令人衰弱的疾病，影响 50% 的糖尿病患者。尽管 DN 的患病率很高，但其确切的生物学机制尚不清楚，也没有阻止疾病的治疗方法。 目前可用。因此，迫切需要确定治疗靶点和预防措施 DN 策略。最近的数据表明，2 型糖尿病 (T2D) 中鞘脂代谢发生改变，导致 非典型神经毒性脱氧鞘脂 (dSL) 的积累。已知 dSL 会在以下设置中增加 低水平的 L-丝氨酸和高水平的 L-丙氨酸，但糖尿病中 dSL 积累的原因是 不知道。重要的是，口服补充 L-丝氨酸可以抑制 dSL 的形成， 改善 DN 动物模型中的神经病变，表明 dSL 可能在 DN 中发挥作用。拟议的研究 旨在定义与 DN 最密切相关的特定 DSL 分子并评估 T2D 中 L-丙氨酸与 L-丝氨酸的比例改变导致 dSL 积累。定义 dSL 中的特定分子 与 DN 最密切相关的途径并了解其形成原因可以 导致针对该疾病的有针对性的治疗干预措施的发展。 先进的质谱技术已用于证明选定 dSL 中的升高（1- 脱氧二氢神经酰胺）在一小群患有病态肥胖、T2D 和 DN 的成年人中。结果表明 1) L- 与对照组相比，DN 受试者的丝氨酸水平较低，L-丙氨酸水平较高； 2）那 L-丙氨酸与 L-丝氨酸比率的增加与 dSL 和 DN 严重程度呈正相关。在目标 1 中 拟议的研究，将使用相同的最先进技术来检查详细的 dSL 图谱和氨基酸 《青少年 T2D 治疗方案》（今日）中的横断面和纵向水平 队列。这些研究将检验 L-丙氨酸与 L-丝氨酸的比例是否与 dSL 积累相关。 青年发病 T2D 的横断面比较（目标 1a）；并测试 L-丙氨酸是否升高至 L-丝氨酸 使用回顾性病例对照研究，比率和 dSL 与患 DN 的几率增加相关 设计（目标 1b）。在目标 2 中，dSL 和 L-丙氨酸与 L-丝氨酸比率与 DN 严重程度之间的相关性为 在科罗拉多大学的成人 T2D 队列（不考虑病态肥胖的混杂因素）中进行了检查 经过验证的 DN 测量，包括皮肤活检中的神经纤维密度。 K23 补助金将允许候选人接受以下方面的培训：1) DN 特定的临床结果测量，2) 流行病学原理和统计方法，3) 脂质生物学和质谱学基础。这 博士的指导和建议。简·鲁施、罗伯特·墨菲、布莱恩·伯格曼、伊娃·费尔德曼和莱斯利·兰格， 他的专业知识涵盖内分泌学、DN、流行病学和脂质生物学，非常适合该项目。这 科罗拉多大学丹佛分校拥有领先的临床研究，为这项工作提供了最佳环境 T2D 计划，以及支持初级研究人员的广泛基础设施。