Nuclear sphingolipid metabolism in regulation of myogenesis

核鞘脂代谢调节肌生成

• 批准号: 9437297
• 负责人: Larry R. Gerace
• 金额: $ 25.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9437297
• 关键词: Address; Animal Model; Apoptosis; Binding; Biochemical; Biochemical Pathway; Cell Fractionation; Cell Nucleus; Cell membrane; Ceramidase; Ceramides; Environment; Enzymes; Functional disorder; Gene Expression; Gene Targeting; Generations; Genes; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Investigation; Ligands; Light; Link; Lipids; Membrane; Metabolism; Modeling; Muscle; Muscular Dystrophies; Myoblasts; Neuromuscular Diseases; Nuclear; Nuclear Envelope; Nuclear Proteins; Nucleic Acid Regulatory Sequences; Pathology; Pathway interactions; Peripheral; Physiological Processes; Process; Production; Proteins; RNA Interference; Regulation; Regulator Genes; Research; Role; Signal Transduction; Signaling Molecule; Sphingolipids; Sphingomyelinase; Sphingosine-1-Phosphate Receptor; Subcellular Fractions; Testing; Work; ceramide 1-phosphate; chromatin immunoprecipitation; improved; insight; knock-down; myogenesis; sphingosine 1-phosphate; sphingosine kinase

Sphingolipids (SLs) are essential structural components of membranes and provide reservoirs for critical bioactive lipids, including ceramide and sphingosine 1-phosphate (S1P). Whereas ceramide is associated with apoptosis and growth arrest, S1P commonly promotes survival and proliferation. The best- characterized targets of S1P are S1P receptors localized to the plasma membrane. S1P also can act in the nucleus by binding to and inhibiting class I histone deacetylases (HDACs), which are major regulators of gene expression. SL signaling is characterized by highly compartmentalized generation and targeting of the bioactive molecules. Substantial insight on localized S1P production and targeting at the plasma membrane has been obtained, but little is known about regulation of SL metabolism in the nucleus. This project involves investigation of proteins with potential roles in generating bioactive SLs in the nucleus. The work includes analysis of a neutral sphingomyelinase localized to the nuclear envelope (NE) that is required for myoblast differentiation, which may be integral to nuclear SL metabolism. This component and other enzymes with potential links to nuclear SL metabolism will be analyzed in a cultured myoblast differentiation model. Subcellular fractionation and lipidomics will be used to characterize the role of these proteins in regulating the dynamic SL landscape of the nucleus during myoblast differentiation, and in producing bioactive SLs including S1P. In addition, the potential functions of S1P in activating expression of myogenic genes as an inhibitory ligand for class I HDACs will be evaluated. Overall this project will investigate the hypothesis that the nucleus houses a distinctive SL metabolism that has a major role in myogenic differentiation. The work has clear relevance to muscle pathology in humans, since HDAC inhibitors including S1P have been shown to ameliorate muscular dystrophies in animal models.

鞘脂（SLS）是膜的必不可少的结构成分，并为关键提供储层 生物活性脂质，包括神经酰胺和1-磷酸盐（S1P）。而神经酰胺是关联的 随着凋亡和生长停滞，S1P通常促进生存和增殖。最好的- S1P的特征靶标是位于质膜的S1P受体。 S1P也可以采取行动 通过与主要调节剂结合并抑制I类组蛋白脱乙酰基酶（HDAC）来结合并抑制I类组蛋白脱乙酰基酶（HDAC） 基因表达。 SL信号传导的特征是高度分室化的生成和靶向 生物活性分子。对局部S1P生产和靶向等离子体的实质性见解 已经获得了膜，但对核中SL代谢的调节知之甚少。这 项目涉及研究在核中生成生物活性SLS的潜在作用的蛋白质。 这项工作包括对位于核包膜（NE）的中性鞘磷脂酶的分析 成肌细胞分化所需的，这可能是核SL代谢不可或缺的一部分。此组件和 在培养的肌细胞中将分析具有与核SL代谢有潜在联系的其他酶 分化模型。亚细胞分馏和脂肪组学将用于表征这些作用 在肌细胞分化过程中调节细胞核动态SL景观时的蛋白质，并在 产生包括S1P在内的生物活性SL。另外，S1P在激活表达中的电势函数 将评估肌原基因作为I类HDAC的抑制配体的。总的来说这个项目将 研究核构成具有独特的SL代谢的假设，该代谢在 肌源分化。这项工作与人类的肌肉病理学明显相关，因为HDAC 包括S1P在内的抑制剂已显示可改善动物模型中的肌肉营养不良。