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Targeting a Ceramide Double Bond to Treat Cardiometabolic Disorders

靶向神经酰胺双键治疗心脏代谢疾病

基本信息

批准号：
10382339
负责人：
SCOTT A SUMMERS
金额：
$ 46.58万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382339
关键词：
Adipose tissue Adult Amino Acids Anabolism Antidiabetic Drugs Atherosclerosis Biological Markers Blood Vessels Cardiac Cardiometabolic Disease Cardiomyopathies Cardiovascular system Cell physiology Ceramidase Ceramides Clinic Complex Cystic Fibrosis Data Deposition Diabetes Mellitus Dose Dyslipidemias Enzymes Event Fatty Acids Fatty Liver Fatty acid glycerol esters Fenretinide Functional disorder Gangliosides Genes Genetic Glucose Health Heart Diseases Heart failure Hepatic Hepatocyte Human Hypertension Hypertriglyceridemia In Vitro Individual Insulin Resistance Intervention Intestines Knockout Mice Lead Ligands Lipids Lipoproteins Liver Liver Fibrosis Marketing Measurement Measures Metabolic Metabolic Diseases Metabolic Pathway Metabolism Molecular Mus Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Oncology Overnutrition Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase II Clinical Trials Phenotype Premenopause Production Property Proteomics Protocols documentation Reaction Reagent Retinoids Rodent Rodent Model Safety Serum Signal Pathway Sphingolipids Sphingomyelins Steatohepatitis Testing Therapeutic Tissues Toxic effect Variant adiponectin base cancer clinical trial cardioprotection cardiovascular risk factor clinical biomarkers desaturase dihydroceramide dihydroceramide desaturase drug discovery experience gene therapy glucose metabolism glucose tolerance improved in vivo inhibitor insulin sensitivity insulin sensitizing drugs insulin signaling lipid metabolism liver metabolism minimally invasive mortality nanomolar non-alcoholic fatty liver disease novel novel therapeutics pharmacodynamic biomarker pharmacokinetics and pharmacodynamics physical inactivity pi bond prevent programs receptor targeted biomarker therapeutic target tool

项目摘要

Project 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 block ceramide synthesis in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). Herein we aim to evaluate the therapeutic potential of inhibiting dihydroceramide desaturase-1 (DES1), our preferred target in the ceramide synthesis pathway, in the treatment of insulin resistance and non-alcoholic fatty liver disease. Aims will involve the following: 1. Evaluating the consequences of inhibiting DES1 on metabolic disorders in mice 2. Determining the mechanism by which the subtle molecular changes to ceramides caused by DES1 inhibition alter cellular function Findings obtained from these studies could lead to new pharmacological approaches for treating diabetes and other cardiometabolic diseases.

项目摘要营养过剩和缺乏运动会促进神经酰胺等鞘脂的积累，胰岛素信号传导和合成代谢。实施药物或遗传干预，啮齿类动物的神经酰胺合成可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）。在此，我们旨在评估抑制二氢神经酰胺去饱和酶-1（DES 1）的治疗潜力，DES 1是我们在治疗中的首选靶点。神经酰胺合成途径，用于治疗胰岛素抵抗和非酒精性脂肪肝。旨在将涉及以下方面： 1.评价抑制DES 1对小鼠代谢紊乱的影响 2.确定DES 1引起神经酰胺的细微分子变化的机制抑制改变细胞功能从这些研究中获得的发现可能导致治疗糖尿病的新药理学方法，其他心脏代谢疾病。