Sphingolipids: Regulators of SREBP and lipid metabolism

鞘脂：SREBP 和脂质代谢的调节剂

• 批准号: 7487738
• 负责人: TILLA S WORGALL
• 金额: $ 12.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487738
• 关键词: 1,2-diacylglycerol; Address; Adult; Affect; Aging; Alzheimer' s Disease; Binding Proteins; Cardiovascular system; Cell Death; Cell Line; Cell Nucleus; Cell Proliferation Regulation; Cell Survival; Cells; Ceramides; Chinese Hamster Ovary Cell; Cholesterol; Cholesterol Esters; Confocal Microscopy; Coronary Arteriosclerosis; Data; Diglycerides; Endopeptidases; Endoplasmic Reticulum; Enzymes; Fatty Acids; Feedback; Fibroblasts; Genes; Genetic Transcription; Goals; Golgi Apparatus; Hereditary Sensory Neuropathy; Lipids; Mediating; Modeling; Morbidity - disease rate; Mutation; Neurodegenerative Disorders; Neurons; Neuropathy; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peripheral Nerves; Physiological; Plasma; Play; Protein Overexpression; Public Health; Range; Rate; Regulation; Regulatory Element; Research Personnel; Risk Factors; Role; Serine; Small Interfering RNA; Sphingolipids; Sphingomyelins; Sterols; Therapeutic; Therapeutic Intervention; Transcription factor genes; Transferase; Transgenic Organisms; Triglyceride Metabolism; Triglycerides; acid sphingomyelinase; aging population; analog; cardiovascular risk factor; inhibitor/antagonist; interest; intracellular protein transport; lipid metabolism; novel; novel therapeutics; programs; protein kinase D; protein metabolism; protein transport; sphingomyelin synthase; sphingosine kinase; therapeutic target; trafficking; transcription factor

DESCRIPTION (provided by applicant): The focus of this proposal is to study the relationship between sphingolipid synthesis and sterol regulatory element binding-proteins (SREBP), key transcription factors of lipid metabolism. SREBP and sphingolipid related pathways contribute significantly to the morbidity related to cardiovascular and neurodegenerative diseases and are thus specifically relevant to the aging population. Cholesterol and sphingomyelin are independent risk factors for coronary artery disease. We recently showed that sphingolipid synthesis correlates with SRE-mediated gene transcription. Current data show that serine-palmitoyl transferase (SPT), the rate-limiting enzyme of sphingolipid de-novo synthesis is essential in the feedback regulation of SREBP. Together, these mechanisms are likely relevant in hereditary sensory neuropathy (HSN), caused by mutations in a subunit of SPT. Our data in HSN cells demonstrate increased SRE-mediated gene transcription, cholesterol synthesis and mass and indicate altered cellular cholesterol transport. We demonstrate that sphingolipid mediated regulation of SREBP-related pathways differs significantly in neuronal cells. We also demonstrate that diacylglycerol, a metabolite of sphingolipid synthesis, affects the cellular trafficking of SREBP. The central hypothesis is that sphingolipid synthesis is critical in the regulation of SREBP metabolism. The overall goal of the project is to investigate mechanism(s) how sphingolipid synthesis affects SREBP metabolism. We propose to develop fibroblasts and neuronal cell lines in which sphingolipid synthesis can be systematically modified using inducible siRNA and overexpression strategies of key enzymes. We will also assess the role of inhibitors and feedback regulators of sphingolipid synthesis on the regulation of SREBP-related lipid metabolism (aim 1). We will use fluorescent confocal microscopy to investigate the role sphingolipid synthesis and metabolites of sphingolipid synthesis on SREBP trafficking (aim 2). Results are expected to identify novel regulatory mechanisms that contribute to the pathogenesis of cardiovascular and neurodegenerative diseases and are amenable to therapeutic intervention. We identified a pathway that regulates important risk factors for cardiovascular and neurodegenerative diseases. We propose to further investigate this pathway to identify mechanisms that could be novel therapeutic targets - a desirable therapeutic goal in the interest of public health.

描述(申请人提供)：本建议的重点是研究鞘脂脂合成与固醇调节元件结合蛋白(SREBP)之间的关系，SREBP是脂代谢的关键转录因子。SREBP和鞘磷脂相关通路对心血管和神经退行性疾病的发病率有很大贡献，因此与老龄化人口特别相关。胆固醇和鞘磷脂是冠状动脉疾病的独立危险因素。我们最近发现鞘磷脂的合成与SRE介导的基因转录相关。目前的资料表明，丝氨酸棕榈酰转移酶(SPT)是鞘磷脂从头合成的限速酶，在SREBP的反馈调节中起着至关重要的作用。总之，这些机制可能与遗传性感觉神经病(HSN)有关，HSN是由SPT亚单位的突变引起的。我们在HSN细胞中的数据显示，SRE介导的基因转录、胆固醇合成和质量增加，并表明细胞胆固醇运输发生了变化。我们证明神经细胞中鞘磷脂对SREBP相关通路的调节有显著的不同。我们还证明了神经鞘糖脂合成的代谢物二酰甘油影响SREBP的细胞转运。中心假说是鞘磷脂的合成在调节SREBP代谢中起着关键作用。该项目的总体目标是研究鞘磷脂合成如何影响SREBP代谢的机制(S)。我们建议发展成纤维细胞和神经细胞系，在这些细胞系中，神经鞘脂脂的合成可以使用可诱导的siRNA和关键酶的过度表达策略进行系统的修饰。我们还将评估鞘磷脂合成的抑制剂和反馈调节剂在调节SREBP相关脂代谢方面的作用(目标1)。我们将使用荧光共聚焦显微镜来研究鞘磷脂合成和代谢产物对SREBP运输的作用(目标2)。预计结果将确定新的调控机制，这些机制有助于心血管和神经退行性疾病的发病机制，并易于进行治疗干预。我们确定了一条调节心血管和神经退行性疾病的重要风险因素的途径。我们建议进一步研究这一途径，以确定可能成为新的治疗靶点的机制--这是一个符合公共卫生利益的理想治疗目标。