Targeting a Ceramide Double Bond to Treat Cardiometabolic Disorders

项目摘要 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以阻断 啮齿动物神经酰胺的合成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)。在此，我们的目标是 评估抑制二氢神经酰胺脱饱和酶-1(DES1)的治疗潜力，DES1是我们在 神经酰胺合成途径，在治疗胰岛素抵抗和非酒精性脂肪性肝病中的作用。目标 将涉及以下内容： 1.评价抑制DES1对小鼠代谢紊乱的影响 2.确定DES1引起神经酰胺分子细微变化的机制 抑制改变细胞功能 这些研究的发现可能导致治疗糖尿病和糖尿病的新的药理学方法 其他心脏代谢性疾病。

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.