Ceramide and cardiovascular risk in obesity

肥胖症中的神经酰胺和心血管风险

• 批准号: 6821011
• 负责人: FAHUMIYA SAMAD
• 金额: $ 49.14万
• 依托单位: LA JOLLA INST FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821011
• 关键词: adipocytes; adipose tissue; biological signal transduction; cardiovascular disorder risk; ceramides; gene induction /repression; genetically modified animals; hyperinsulinism; in situ hybridization; laboratory mouse; obesity; pathogenic diet; plasminogen activator inhibitors; polymerase chain reaction; sphingosine; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Obesity is reaching epidemic proportions in western societies and over 65% of the adult U.S. population is either overweight or obese and will likely suffer clinical cardiovascular complications in the years ahead. In order to develop rational therapeutic approaches to treat the cardiovascular conditions attributable to obesity we need to first develop a comprehensive understanding of the molecular mechanisms of obesity-associated cardiovascular risk. Recent studies have documented the importance of the lipid second messenger, ceramide, in a variety of disorders including obesity, diabetes and atherosclerosis. The overall goal of this proposal is to use the pro-thrombotic cardiovascular risk gene, plasminogen activator inhibitor-1 (PAl-l), as a read out, to evaluate the role played by ceramide in the cardiovascular risk associated with obesity. In Aim 1 we will initially test the hypothesis that the levels of ceramide itself are elevated in adipose tissues in obesity, and that the hyperinsulinemia and elevated TNF-alpha associated with obesity contribute to this increase. In Aim 2, we will use PAl-1 as a read-out to test the hypothesis that ceramide and/or its bioactive metabolites, sphingosine and sphingosine-l-phosphate, are important regulators of cardiovascular risk in obesity, and that this pathway also contributes to obesity-associated increase in PAl-1 mediated by insulin and TNF-alpha. We also will determine signaling mechanisms that link ceramide to PAl-1 expression in the adipocyte. Finally, in Aim 3, we will test the hypothesis that membrane-bound TNF-alpha in the adipose tissue/adipocytes is an important mediator of increased ceramide and PAl-1 in obesity. These studies will not only advance our understanding of the molecular mechanisms that contribute to the induction of PAl-l, a gene that is consistently up regulated in obesity and positively correlated with cardiovascular risk, but will be clinically significant as they may directly identify novel pathways that link obesity to increased cardiovascular risk.

描述（由申请人提供）：肥胖在西方社会达到流行病的程度，超过65%的美国成年人超重或肥胖，并可能在未来几年遭受临床心血管并发症。为了开发合理的治疗方法来治疗由肥胖引起的心血管疾病，我们需要首先全面了解肥胖相关心血管风险的分子机制。最近的研究已经证明了脂质第二信使神经酰胺在包括肥胖、糖尿病和动脉粥样硬化在内的各种疾病中的重要性。本提案的总体目标是使用促血栓性心血管风险基因，纤溶酶原激活物抑制剂-1 （pal -1）作为读取值，评估神经酰胺在肥胖相关心血管风险中的作用。在Aim 1中，我们将初步验证肥胖患者脂肪组织中神经酰胺本身水平升高的假设，以及与肥胖相关的高胰岛素血症和tnf - α升高导致这种增加。在Aim 2中，我们将使用PAl-1作为读值来验证神经酰胺和/或其生物活性代谢物，鞘氨醇和鞘氨醇-l-磷酸，是肥胖心血管风险的重要调节因子的假设，并且该途径也有助于胰岛素和tnf - α介导的肥胖相关PAl-1的增加。我们还将确定神经酰胺与脂肪细胞中PAl-1表达之间的信号机制。最后，在Aim 3中，我们将验证脂肪组织/脂肪细胞中膜结合的tnf - α是肥胖中神经酰胺和PAl-1增加的重要介质的假设。这些研究不仅将促进我们对诱导pal - 1（一种在肥胖中持续上调并与心血管风险正相关的基因）的分子机制的理解，而且将具有临床意义，因为它们可能直接确定将肥胖与心血管风险增加联系起来的新途径。