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: 9974766
• 负责人: VERA FRIDMAN
• 金额: $ 19.02万
• 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/9974766
• 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; Future; Goals; Grant; Health Services Accessibility; Hereditary Sensory and Autonomic Neuropathies; High Prevalence; Hyperglycemia; Infrastructure; Intervention; Knowledge; Lead; 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; Plasma; Play; Prevention strategy; Quality of life; Race; 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; clinically relevant; cohort; density; effective therapy; improved; instrument; nerve conduction study; neurotoxic; novel; novel therapeutics; 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.

项目摘要/摘要 糖尿病神经病（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 它的高流行率，DN的精确生物学机制尚不清楚，没有任何疾病的治疗是 目前可用。因此，迫切需要鉴定治疗靶标和预防靶标 DN策略。最近的数据表明，2型糖尿病（T2D）改变了鞘脂代谢，导致 非典型，神经毒性脱氧胆脂（DSL）的积累。已知DSL在环境中增加 低水平的氨基酸L链和高水平的L-丙氨酸，但DSL积累的原因是 不知道。重要的是，用氨基酸L-丝氨酸抑制DSL和 DN动物模型中的神经病改善，表明DSL可以在DN中发挥作用。拟议的研究 旨在定义与DN最紧密相关的特定DSL分子并评估的贡献 L-丙氨酸与L-丝氨酸与DSL在T2D中的积累的改变。定义DSL中的特定分子 与DN最紧密相关的途径，了解其形成的原因可能 导致针对该疾病的靶向治疗干预措施的发展。 晚期质谱技术已用于证明精选DSL的升高（1- 在一小部分患有病态肥胖症的成年人群中，脱氧二氢酰胺），T2D和DN。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-丙氨酸水平更高。 2） L-丙氨酸与L丝氨酸比率的增加与DSL和DN严重程度正相关。在目标1中 拟议的研究，相同的最先进技术将用于检查详细的DSL剖面和氨基酸 在青少年和青年的T2D治疗方案中，在横截面和纵向上的水平（今天） 队列。这些研究将检查L-丙氨酸与L丝氨酸比率是否与DSL积累有关 在横截面比较中的青年发病T2D（AIM 1A）；并测试L-丙氨酸的高程到L-丝氨酸 比率和DSL与回顾性案例对照研究相关的比率增加了DN的几率 设计（AIM 1B）。在AIM 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将是 在科罗拉多大学的成人T2D队列（没有病态肥胖的混杂因素）中检查 经过验证的DN措施，包括皮肤活检的神经纤维密度。 K23赠款将允许候选人在1）特定于DN的临床结果指标中进行培训，2） 流行病学原理和统计方法，以及3）脂质生物学和质谱法的基本原理。这 指导和咨询博士。简·瑞斯（Jane Reusch），罗伯特·墨菲（Robert Murphy），布莱恩·伯格曼（Bryan Bergman），伊娃·费尔德曼（Eva Feldman）和莱斯利·兰格（Leslie Lange） 其专业知识涵盖了内分泌学，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为这项工作提供了最佳的环境，并进行了领先的临床研究 T2D的计划以及支持初级研究人员的广泛基础设施。