Ceramide and cardiovascular risk in obesity

描述(申请人提供)：肥胖正在西方社会流行，超过65%的美国成年人口超重或肥胖，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可归因于肥胖的心血管疾病，我们首先需要全面了解肥胖相关心血管风险的分子机制。最近的研究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。该提案的总体目标是以血栓形成前心血管风险基因纤溶酶原激活物抑制物-1(PAL-L)为读数，评估神经酰胺在肥胖相关心血管风险中所起的作用。在目标1中，我们将初步检验这一假设，即肥胖症患者脂肪组织中神经酰胺水平升高，与肥胖相关的高胰岛素血症和升高的肿瘤坏死因子-α导致这种增加。在目标2中，我们将使用PAL-1作为读数来验证神经酰胺和/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素的假设，以及这一途径也有助于胰岛素和肿瘤坏死因子-α介导的肥胖相关PAL-1的增加。我们还将确定将神经酰胺与脂肪细胞中PAL-1表达联系起来的信号机制。最后，在目标3中，我们将验证这样一个假设，即脂肪组织/脂肪细胞中的膜结合肿瘤坏死因子-α是肥胖中神经酰胺和PAL-1增加的重要介质。这些研究不仅将促进我们对PAL-L基因诱导的分子机制的理解，该基因在肥胖中持续上调，并与心血管风险呈正相关，而且将具有临床意义，因为它们可能直接发现将肥胖与心血管风险增加联系起来的新途径。

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.