Ceramide and cardiovascular risk in obesity

肥胖症中的神经酰胺和心血管风险

• 批准号: 7236688
• 负责人: FAHUMIYA SAMAD
• 金额: $ 38.83万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 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/7236688
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adipocytes; Adipose tissue; Adult; Amines; Atherosclerosis; Binding; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cell Line; Ceramides; Clinical; Condition; Cycloserine; Desipramine; Diabetes Mellitus; Diacylglycerol Kinase; Diet; Disease; Dose; Enzymes; Epidemic; Fatty acid glycerol esters; Fumonisin B1; GW 4869; Gene Expression; Generations; Genes; Goals; Hyperinsulinism; In Situ Hybridization; Insulin; Leptin; Link; Lipids; MAPK14 gene; Measures; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Mitogen-Activated Protein Kinases; Molecular; Mus; N-caproylsphingosine; Numbers; Obese Mice; Obesity; Overweight; Pathway interactions; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Plasma; Plasminogen Activator Inhibitor 1; Population; Process; Production; Protein phosphatase; Reaction Time; Reading; Recombinants; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Role playing therapy; Second Messenger Systems; Serine; Signal Pathway; Signal Transduction; Societies; Sphingomyelinase; Sphingosine; TNF gene; TNF-alpha converting enzyme; Testing; Therapeutic; Time; Transferase; Transgenic Mice; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; acid sphingomyelinase; base; cardiovascular risk factor; clinically significant; enzyme activity; galactosylgalactosylglucosylceramidase; human TNF protein; inhibitor/antagonist; inorganic phosphate; lipid mediator; mutant; neutralizing antibody; novel; programs; receptor; research study; second messenger

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）：肥胖症在西方社会中达到流行比例，超过65％的美国人口超重或肥胖，并且可能在未来几年中遭受临床心血管并发症。为了开发理性的治疗方法来治疗可归因于肥胖症的心血管疾病，我们首先需要对肥胖相关心血管风险的分子机制进行全面的了解。最近的研究记录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多种疾病中的重要性。该提案的总体目的是使用读出的促血栓性心血管危险基因，纤溶酶原激活剂1（PAL-L），以评估神经酰胺在与肥胖相关的心血管风险中所起的作用。在AIM 1中，我们最初将检验以下假设：肥胖症中脂肪组织中神经酰胺的水平升高，并且与肥胖有关的高胰岛素血症和升高的TNF-α升高会导致这种增加。在AIM 2中，我们将使用PAL-1作为读出来，以测试神经酰胺和/或其生物活性代谢产物，鞘氨醇和鞘氨醇-L磷酸盐是肥胖症中心血管风险的重要调节剂，而这种途径也对肥胖症介导的Pal-1促进胰岛素和Tnf-Alpha介导的肥胖相关增加。我们还将确定将神经酰胺与脂肪细胞中的PAL-1表达联系起来的信号传导机制。最后，在AIM 3中，我们将检验以下假设：脂肪组织/脂肪细胞中膜结合的TNF-α是肥胖症中神经酰胺和PAL-1增加的重要介体。这些研究不仅会提高我们对有助于诱导PAL-L的分子机制的理解，PAL-L（该基因一直受到肥胖症的调节，并与心血管风险呈正相关，但在临床上会很重要，因为它们可能直接识别肥胖症与增加心血管风险增加的新型途径。