Sphingolipid Metabolism in Drosophila Development

果蝇发育中的鞘脂代谢

基本信息

批准号：
8423071
负责人：
JULIE D SABA
金额：
$ 32.2万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423071
关键词：
Actins Address Adult Animal Model Apoptosis Atrophic Autophagocytosis Bacterial Infections Biochemical Biochemistry Biological Biological Models Biology Cardiomyopathies Catabolism Cell Line Cell Proliferation Cell Survival Cell model Cells Cellular Stress Response Cellular biology Chemicals Chest Complex Defect Development Differentiation and Growth Disease Drosophila genus Drosophila melanogaster Dynamin Dystroglycan Endocytosis Engineering Enzymes Eukaryota Event Evolution Extracellular Matrix Family Gene Expression Gene Targeting Genetic Goals Grant Growth Growth and Development function Homeostasis Hybrids Inflammation Inherited Injury Insulin Resistance Investigation Knockout Mice Lipids Lyase Maintenance Malignant Neoplasms Medical Membrane Membrane Biology Membrane Fusion Membrane Proteins Metabolic syndrome Metabolism Molecular Molecular Target Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscular Atrophy Muscular Dystrophies Musculoskeletal Diseases Myoblasts Myogenin Myopathy Myosin Heavy Chains Natural regeneration Neurodegenerative Disorders Organ PI3K/AKT Pathology Pathway interactions Pattern Phenocopy Phenotype Phosphorylation Physiological Play Process Production Protein Biosynthesis Protein-Lysine 6-Oxidase Proteins Proto-Oncogene Proteins c-akt Research Rodent Model Role SPHK1 enzyme Sarcolemma Signal Transduction Signaling Molecule Signaling Protein Skeletal Muscle Sphinganine-1-phosphate aldolase Sphingolipids Sphingosine-1-Phosphate Receptor Striated Muscles System Testing Time Tissues Translations Vertebral column Virus Diseases Wasting Syndrome Work age related base cancer therapy embryo tissue enzyme activity experience fly frailty gene therapy human disease immune function migration muscle regeneration muscular dystrophy mouse model mutant novel pre-clinical prevent protein expression public health relevance response satellite cell sphingosine 1-phosphate sphingosine kinase sphingosine-1-phosphate lyase

项目摘要

DESCRIPTION (provided by applicant): Sphingolipids are a conserved family of lipids built upon a sphingoid base backbone. Sphingolipids serve structural membrane functions, whereas their metabolism produces signaling molecules involved in regulating mammalian development, immune function, inflammation and cellular stress responses. Studies supported by this grant have explored the role of sphingolipids in the model organism Drosophila melanogaster. These studies have resulted in the chemical characterization of Drosophila sphingoid bases and the identification of novel endogenous Drosophila sphingolipids with potent growth-inhibitory activity. Further, we have shown that Sply mutants lacking expression of Drosophila sphingosine-1-phosphate (S1P) lyase (SPL), which is responsible for the final step of sphingolipid degradation, accumulate sphingolipid intermediates and develop a progressive myopathy in the thoracic muscles needed to power flight. The Sply myopathy is corrected by reducing sphingolipid production, indicating sphingolipid intermediates play a causative role. We have observed that mutants in key membrane proteins such as dynamin and dystroglycan phenocopy the Sply myopathy. We have also conducted cell-based investigations that suggest that Sply/SPL is required for normal AKT signaling, protein translation, myoblast fusion, myoblast gene expression and control of autophagy. Many of these interactions have been corroborated in murine C2C12 cells, indicating that SPL plays a conserved role in myoblast survival, fusion and differentiation. We have also found that sphingosine kinase and S1P lyase are dynamically upregulated during murine muscle regeneration, leading to a transient peak in S1P levels in regenerating muscle. These collective observations have led us to propose our central hypothesis, which states that SPL plays a critical role in muscle biology, development and homeostasis. The specific aims of our proposal are, thus: 1) To define the role of SPL in muscle cell biology; 2) To dissect the role of SPL in muscle development; and 3) To establish the role of SPL in muscle atrophy and regeneration. Our long-term goals are to exploit Drosophila to elucidate the role of sphingolipids in biology, membrane function, and tissue homeostasis and to define the relevance of these findings to human disease. Due to species-specific structural differences in sphingolipids and the lack of S1P receptors in lower eukaryotes, we do not expect the two systems to be equivalent. Thus, our goals are to compare the biochemical and molecular events associated with SPL loss in Drosophila and murine cell and animal models, with the intent of developing a comprehensive understanding of how SPL functions in the context of muscle tissue and how its function may have been modified throughout evolution. These studies should be readily achieved by our team, which has extensive experience in sphingolipid biochemistry, Drosophila genetics, and the genetics and pathology of MD.

描述（由申请人提供）：鞘脂是建立在鞘脂底座上的脂质家族。鞘脂具有结构性膜功能，而它们的代谢产生参与调节哺乳动物发育，免疫功能，炎症和细胞应激反应的信号分子。该赠款支持的研究探索了鞘脂在模型有机体果蝇中的作用。这些研究导致了果蝇鞘脂碱的化学表征，并鉴定出具有有效的生长活性的新型内源性果蝇鞘脂。此外，我们已经表明，缺乏果蝇鞘氨醇1-磷酸（S1P）裂解酶（SPL）表达的Sply突变体负责鞘脂降解的最后一步，积累了鞘脂的中间体，并在需要进行动力飞行的胸肌肌肉中产生了渐进性肌病。通过减少鞘脂的产生来纠正SPLY肌病，表明鞘脂中间体起因作用。我们已经观察到关键膜蛋白中的突变体（例如dynamin和Dystroglycan苯并copicy sply肌病）。我们还进行了基于细胞的研究，表明正常AKT信号传导，蛋白质翻译，成肌细胞融合，成肌细胞基因表达和自噬的控制所必需。这些相互作用中的许多相互作用已在鼠C2C12细胞中证实，表明SPL在成肌细胞存活，融合和分化中起着保守的作用。我们还发现，在鼠肌肉再生过程中，鞘氨醇激酶和S1P裂解酶动态上调，导致在再生肌肉中S1P水平的短暂峰。这些集体观察结果使我们提出了我们的中心假设，该假设指出，SPL在肌肉生物学，发育和稳态中起着至关重要的作用。因此，我们提案的具体目的是：1）定义SPL在肌肉细胞生物学中的作用； 2）剖析SPL在肌肉发育中的作用； 3）确定SPL在肌肉萎缩和再生中的作用。我们的长期目标是利用果蝇，以阐明鞘脂在生物学，膜功能和组织稳态中的作用，并确定这些发现与人类疾病的相关性。由于物种特异性的结构差异在鞘脂脂质以及较低的真核生物中缺乏S1P受体的情况下，我们不希望这两个系统是等效的。因此，我们的目标是比较与果蝇和鼠类细胞和动物模型中SPL损失相关的生化和分子事件，以便对SPL在肌肉组织的背景下的功能以及在整个进化过程中如何修改其功能的全面了解。这些研究应很容易由我们的团队来实现，该研究在鞘脂生物化学，果蝇遗传学以及MD的遗传学和病理方面具有丰富的经验。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

S1P lyase in skeletal muscle regeneration and satellite cell activation: exposing the hidden lyase.

DOI：
10.1016/j.bbalip.2012.06.009
发表时间：
2013-01
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Saba JD;de la Garza-Rodea AS
通讯作者：
de la Garza-Rodea AS

A facile stable-isotope dilution method for determination of sphingosine phosphate lyase activity.

DOI：
10.1016/j.chemphyslip.2015.09.006
发表时间：
2016-01
期刊：
Chemistry and physics of lipids
影响因子：
3.4
作者：
Suh JH;Eltanawy A;Rangan A;Saba JD
通讯作者：
Saba JD

Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism.

DOI：
10.1038/srep37064
发表时间：
2016-11-24
期刊：
Scientific reports
影响因子：
4.6
作者：
Mitroi DN;Deutschmann AU;Raucamp M;Karunakaran I;Glebov K;Hans M;Walter J;Saba J;Gräler M;Ehninger D;Sopova E;Shupliakov O;Swandulla D;van Echten-Deckert G
通讯作者：
van Echten-Deckert G