Regulation of Ceramide Synthase by Protein-Protein Interaction

蛋白质-蛋白质相互作用对神经酰胺合酶的调节

• 批准号: 10662299
• 负责人: Can Emre Senkal
• 金额: $ 34.53万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662299
• 关键词: Area; Biochemical; Biological; Biology; Cell Death; Cells; Ceramides; Charcot-Marie-Tooth Disease; Chemoresistance; Data; Diabetes Mellitus; Disease; Down-Regulation; Enzymes; Generations; Goals; Growth; Heat shock proteins; In Vitro; Induction of Apoptosis; Innovative Therapy; Knowledge; Link; Lipids; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mediator; Metabolism; Methods; Mitochondria; Molecular; Mutation; Neurons; PUVA Photochemotherapy; Pathologic; Pathology; Pathway interactions; Phosphorylation; Play; Process; Production; Prognosis; Proteins; Proteomics; Regulation; Role; Scheme; Signal Transduction; Small Interfering RNA; Sphingolipids; Tertiary Protein Structure; Testing; Therapeutic; Vertebral column; cancer cell; chemotherapy; design; dihydroceramide desaturase; gain of function; inhibitor; loss of function; neuron development; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; protein protein interaction; response; tumor growth

Title: REGULATION OF CERAMIDE SYNTHASE BY PROTEIN-PROTEIN INTERACTION Abstract: Ceramides form the backbone of all sphingolipids, and ceramide synthases (CerS) are critical enzymes for de novo production of ceramides. In spite of the key role of CerS in ceramide generation, there is a serious deficiency in understanding how these enzymes are regulated. The long-term goal of this project is to uncover and understand the fundamental molecular mechanisms of how CerS enzymes are regulated. Using a proteomics approach, we discovered that the small heat shock protein Hsp27 interacts specifically with CerS1. Based on our preliminary data we generated the novel hypothesis that Hsp27 is a negative regulator of CerS1 activity via direct interaction that can be modulated by p38-MK2 MAPK mediated phosphorylation of Hsp27, and that down-regulation of Hsp27 induces CerS1/C18:0-ceramide mediated cellular responses. To test this hypothesis, we propose the following Specific Aims: Aim 1: Define the biochemical significance of Hsp27 mediated CerS1 regulation in cells with respect to sphingolipid metabolism and signal transduction. Aim 2: Define the biological significance of Hsp27 mediated CerS1 regulation. Aim 3: Determine the mechanism of Hsp27- CerS1 protein-protein interaction. Overall, these studies will establish Hsp27 as an endogenous modulator of CerS1 and uncover a novel mechanism of how Hsp27 regulates CerS1 and CerS1/C18:0-ceramide governed mitophagy and cancer cell death. The knowledge generated from this study will help design mechanism-based novel therapies against cancer and other pathologies in which C18:0-ceramide is the key mediator by identifying new methods to modulate CerS1 activity.

标题：通过蛋白质 - 蛋白质相互作用调节神经酰胺合酶 抽象的： 神经酰胺形成了所有作为鞘脂的骨架，而神经酰胺合酶（CER）是关键酶 用于从头生产神经酰胺。尽管CER在神经酰胺一代中的关键作用，但还是很严重的 缺乏理解这些酶的调节方式。该项目的长期目标是发现 并了解如何调节CERS酶的基本分子机制。使用 蛋白质组学方法，我们发现小热休克蛋白HSP27与CERS1专门相互作用。 基于我们的初步数据，我们生成了新的假设，即HSP27是CERS1的负调节剂 通过直接相互作用的活动，可以通过p38-MK2 MAPK介导的Hsp27和 HSP27的下调诱导CERS1/C18：0-陶瓷介导的细胞反应。测试这个 假设，我们提出以下特定目的：目标1：定义HSP27的生化意义 在细胞中介导的CERS1调节有关鞘脂代谢和信号转导。目标2：定义 HSP27介导的CERS1调节的生物学意义。 AIM 3：确定HSP27-的机制 CERS1蛋白 - 蛋白质相互作用。总体而言，这些研究将建立HSP27作为内源调节剂 CERS1并发现了HSP27如何调节CERS1和CERS1/C18的新机制 线粒体和癌细胞死亡。这项研究产生的知识将有助于设计基于机制的知识 针对癌症和其他病理的新型疗法，其中C18：0-陶瓷是通过识别的关键介体 调节CERS1活动的新方法。