Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy

糖尿病前期和神经病变中的鞘脂和脂肪酸生物学

• 批准号: 10476670
• 负责人: Amy E. Rumora
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476670
• 关键词: Affect; American; Apoptosis; Biology; Ceramides; Complication; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Neuropathies; Dietary Intervention; Disease; Dyslipidemias; Economic Burden; Fatty Acids; Foundations; Future; Goals; High Fat Diet; Image; In Vitro; Individual; Knockout Mice; Limb structure; Lipids; Mediating; Mentors; Metabolic; Mitochondria; Monounsaturated Fatty Acids; Morphology; Motor; Mus; Nerve; Nervous System control; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Obese Mice; Obesity; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phase; Plasma; Play; Prediabetes syndrome; Prevalence; Research; Role; Saturated Fatty Acids; Sensory; Severities; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids; Spinal Ganglia; Structure; Supplementation; Symptoms; Testing; Toxic effect; Training; Transcript; Type 2 diabetic; United States; Unsaturated Fatty Acids; afferent nerve; base; career; diet-induced obesity; dihydroceramide desaturase; efficacy evaluation; fatty acid supplementation; improved; in vivo; lipidomics; mitochondrial dysfunction; mouse model; neurotoxic; neurotoxicity; new therapeutic target; peripheral nerve damage; prevent; sciatic nerve; sural; sural nerve; targeted treatment; therapeutic target; transcriptomics

ABSTRACT Prediabetes – a condition that precedes type 2 diabetes – affects more than 80 million Americans. Peripheral neuropathy is a diabetic complication that results in a loss of sensation in the limbs due to peripheral nerve damage, and it can develop in both type 2 diabetic as well as prediabetic patients. Despite the prevalence and severity of peripheral neuropathy, there are currently no disease-modifying options. Novel therapeutic targets are therefore of critical importance for future treatments. Dyslipidemia is characterized by increased levels of saturated fatty acids in the plasma, resulting in altered levels of sphingolipids. Ceramides are one type of sphingolipid that are lipotoxic to neurons. Accumulation of saturated fatty acids leads to mitochondrial dysfunction, and cellular apoptosis and may play a central role in the development of peripheral neuropathy. However, monounsaturated fatty acids protect neurons from ceramide-mediated toxicity in vitro, likely via the formation of intracellular lipid droplets. Reversal of ceramide accumulation using monounsaturated fatty acid supplementation may therefore be an effective strategy for normalizing ceramide profiles and preventing peripheral neuropathy. We hypothesize that peripheral neuropathy in prediabetes is the result of toxic ceramide accumulation in neurons in vivo. We further hypothesize that supplementing prediabetic mice with monounsaturated fatty acids will enhance lipid droplet synthesis in neurons to prevent ceramide accumulation and subsequent neurotoxicity. We will test these hypotheses by: 1) determining the ceramide profile of prediabetic mice with neuropathy in both plasma and peripheral nerves, 2) evaluating the efficacy of monounsaturated fatty acid supplementation on ceramide accumulation in prediabetic mice during neuropathy, and 3) determining the mechanisms by which ceramides damage the peripheral nervous system as well as determining the mechanisms by which monounsaturated fatty acid ameliorate this damage. Together, these studies will demonstrate that dyslipidemia plays a central role in the development of peripheral neuropathy and provide an immediate therapeutic target for future treatments.

摘要