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The Role of Ceramides in Skeletal Muscle

神经酰胺在骨骼肌中的作用

基本信息

批准号：
9814051
负责人：
SCOTT A SUMMERS
金额：
$ 4.39万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9814051
关键词：
Ablation Anabolism Antidiabetic Drugs Atherosclerosis Atrophic Bed rest Biological Biological Assay Cardiomyopathies Cardiovascular Diseases Cell model Cells Ceramides Chronic Disease Complement Complex Data Diabetes Mellitus Disease Enzyme Inhibitor Drugs Enzymes Family Fatty acid glycerol esters Functional disorder Gene Expression Profiling Genomics Growth Health Heart Diseases Hindlimb Suspension Human Hypertension Hypertriglyceridemia Impairment Individual Insulin Insulin Resistance Intervention Studies Intestinal permeability Journals Knockout Mice Label Lead Link Lipids Measures Metabolic Metabolic Diseases Metabolism Methods Mitochondria Modeling Monitor Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overlapping Genes Overnutrition Pathology Pathway interactions Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiology Positioning Attribute Property Proteins Proteomics Protocols documentation Reagent Research Personnel Rodent Role Safety Serine Skeletal Muscle Solubility Sphingolipids Steatohepatitis TLR4 gene Techniques Testing Therapeutic Tissues Vertebral column Work adiponectin aqueous base cardioprotection cell growth cell type clinically relevant combat desaturase detection of nutrient dihydroceramide dihydroceramide desaturase feeding galactosylgalactosylglucosylceramidase gene therapy glucose disposal glucose uptake improved inhibitor/antagonist insulin sensitivity insulin sensitizing drugs insulin signaling mouse model muscle metabolism nanomolar novel novel therapeutic intervention novel therapeutics oxidation phosphoproteomics physical inactivity prevent proteomic signature response serine palmitoyltransferase skeletal muscle metabolism small molecule inhibitor stem therapeutic target tool transcriptomics

项目摘要

SUMMARY Overnutrition and physical inactivity promote the accumulation of sphingolipids such as ceramides which block insulin signaling and anabolic metabolism. Implementation of pharmacological or genetic interventions to reduce sphingolipid levels in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). To elucidate the tissue-specific mechanisms through which ceramides contribute to these diseases, we have produced mice allowing for the conditional, cell-type restricted ablation of enzymes required for ceramide biosynthesis or degradation (i.e. serine palmitoyltransferase and dihydroceramide desaturases-1) or degradation (i.e. acid ceramidase). We will apply these tools to dissect the regulatory mechanisms controlling ceramide synthesis and action in skeletal muscle. Aims of the project include the following:  To use these novel mouse models to evaluate the effect of muscle-specific ceramide depletion or induction on insulin sensitivity, muscle growth, and genomic/proteomic signatures under conditions of overnutrition and inactivity.  To apply a ceramide flux assay in isolated human myotubes to identify the regulatory mechanisms that influence rates of ceramide biosynthesis; and,  To determine the efficacy of a new class of inhibitors of dihydroceramide desaturases-1, our preferred target in the ceramide synthesis pathway, as therapeutics that improve muscle insulin sensitivity and prevent muscle loss in rodents. Findings obtained from these studies could uncover new nutrient-sensing machinery that modulates insulin sensitivity and muscle growth. Moreover, the translational component could lead to new pharmacological approaches for improving muscle health.

摘要营养过剩和缺乏体力活动会促进神经酰胺等鞘磷脂的积累，而神经酰胺会阻碍胰岛素信号和合成代谢。实施药物或遗传干预措施，以减少啮齿动物体内的鞘脂水平可以预防或逆转一系列令人印象深刻的代谢病理(如胰岛素抵抗、糖尿病、脂肪性肝炎、高血压、心肌病和动脉粥样硬化)。为了澄清神经酰胺导致这些疾病的组织特异性机制，我们已经产生了小鼠允许对神经酰胺生物合成所需的酶进行有条件的、细胞型限制性消融或降解(即丝氨酸棕榈酰转移酶和二氢神经酰胺脱饱和酶-1)或降解(即酸神经酰胺酶)。我们将应用这些工具来剖析控制神经酰胺合成和在骨骼肌中的作用。该项目的目标包括： 使用这些新的小鼠模型来评估肌肉特异性神经酰胺耗竭或对胰岛素敏感性、肌肉生长和基因组/蛋白质组特征的诱导营养过剩和缺乏运动。 将在离体人肌管中应用神经酰胺流量分析，以确定影响神经酰胺生物合成的速率；以及 确定一类新的二氢神经酰胺去饱和酶-1抑制剂的疗效，我们的首选神经酰胺合成途径的靶点，作为改善肌肉胰岛素敏感性和防止啮齿类动物的肌肉损失。从这些研究中获得的发现可能会发现调节胰岛素的新的营养感应机制敏感度和肌肉生长。此外，翻译成分可能导致新的药理作用改善肌肉健康的方法。