Sphingolipids: Regulators of SREBP and lipid metabolism

鞘脂：SREBP 和脂质代谢的调节剂

• 批准号: 7031467
• 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/7031467
• 关键词: CHO cells; Golgi apparatus; binding proteins; cardiovascular disorder risk; cell line; confocal scanning microscopy; diacylglycerols; endoplasmic reticulum; fluorescence microscopy; gene induction /repression; genetic transcription; hereditary sensory neuropathy; lipid biosynthesis; lipid metabolism; neural degeneration; pathologic process; protein kinase; protein localization; small interfering RNA; sphingolipids; sterols; 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（由申请人提供）：本提案的重点是研究鞘脂合成与固醇调节元件结合蛋白（SREBP）（脂质代谢的关键转录因子）之间的关系。SREBP和鞘脂相关通路显著促进与心血管和神经退行性疾病相关的发病率，因此与老龄化人群特别相关。胆固醇和鞘磷脂是冠心病的独立危险因素。我们最近发现鞘脂合成与SRE介导的基因转录相关。目前的数据表明，丝氨酸棕榈酰转移酶（SPT），鞘脂从头合成的限速酶是必不可少的反馈调节SREBP。总之，这些机制可能与由SPT亚基突变引起的遗传性感觉神经病（HSN）有关。我们在HSN细胞中的数据表明SRE介导的基因转录、胆固醇合成和质量增加，并表明细胞胆固醇转运改变。我们证明，鞘脂介导的调节SREBP相关的途径显着不同的神经元细胞。我们还证明，二酰基甘油，鞘脂合成的代谢产物，影响SREBP的细胞运输。中心假设是鞘脂合成在SREBP代谢的调节中至关重要。该项目的总体目标是研究鞘脂合成如何影响SREBP代谢的机制。我们建议开发成纤维细胞和神经元细胞系，其中鞘脂合成可以使用诱导型siRNA和关键酶的过表达策略进行系统修饰。我们还将评估鞘脂合成的抑制剂和反馈调节剂对SREBP相关脂质代谢的调节作用（目的1）。我们将使用荧光共聚焦显微镜来研究鞘脂合成和鞘脂合成的代谢产物对SREBP运输的作用（目的2）。结果预计将确定新的调节机制，有助于心血管和神经退行性疾病的发病机制，并适合治疗干预。我们确定了一种调节心血管和神经退行性疾病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。