Sphingolipid signaling in mitochondrial surveillance

线粒体监测中的鞘脂信号传导

• 批准号: 10468858
• 负责人: DEREK SIEBURTH
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468858
• 关键词: Animal Model; Behavioral; Biological; Biological Process; Caenorhabditis elegans; Cardiovascular Diseases; Cell physiology; Cells; Cellular Stress Response; Complex; Development; Disease; Ensure; Fibroblast Growth Factor; Generations; Genetic; Genetic Transcription; Goals; Homeostasis; Inflammation; Intestines; Kinetics; Laboratories; Lead; Lipids; Malignant Neoplasms; Mediator of activation protein; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Nervous system structure; Neurodegenerative Disorders; Neurons; Neuropeptides; Neurosecretory Systems; Organism; Orthologous Gene; Outer Mitochondrial Membrane; Peptides; Physiological Processes; Production; Protein Isoforms; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Sphingolipids; Sphingosine; Stress; Stroke; Testing; cellular targeting; design; experimental study; gene function; in vivo; mitochondrial membrane; neurotransmitter release; novel; programs; protective effect; protein function; proteostasis; recruit; response; sphingosine 1-phosphate; sphingosine kinase; stressor

Project Summary Sphingolipids regulate a multitude of cellular and physiological processes and dysregulation of sphingolipid signaling is associated with cardiovascular and neurodegenerative disorders, and stroke. The long-term goal of the proposed research is to identify the cellular and molecular mechanisms by which sphingosine- 1-phospate (S1P), generated by sphingosine kinase, regulates the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt is critical for maintaining mitochondrial protein homeostasis in response to mitochondrial stress, but molecular mechanisms underlying its activation are not fully understood. My laboratory uses the model C. elegans to study the role of sphingolipid signaling in regulating neuronal function and neurotransmitter release. We recently uncovered a novel function for the sole sphingosine kinase ortholog, SPHK-1, in activating the UPRmt and in promoting organism-wide protection in response to a broad array of mitochondrial stressors. We found that SPHK-1 associates with mitochondria and that this association is regulated by mitochondrial stress generated either cell autonomously (in the intestine) or cell non-autonomously (by the nervous system). Here we seek to uncover the cellular and molecular mechanisms by which sphingolipid signaling is regulated during the UPRmt, how it activates the UPRmt and how it impacts mitochondrial homeostasis and survival in multicellular organisms. In Aim 1, we determine the molecular mechanism by which mitochondrial stress regulates SPHK-1 targeting and function. In Aim 2, we determine how neuroendocrine signaling regulates sphingolipid signaling during the UPRmt. In Aim 3, we identify cellular targets of S1P during the UPRmt and how they regulate transcriptional responses to ensure proper cellular homeostasis and survival in the face of stress. This proposal will advance mechanistic understanding of how mitochondrial sphingosine kinase is regulated and signals in vivo, and will further understanding of the mechanism underlying activation of the UPRmt.

项目概要 鞘脂调节多种细胞和生理过程以及鞘脂的失调 信号传导与心血管和神经退行性疾病以及中风有关。长期来看 拟议研究的目标是确定鞘氨醇的细胞和分子机制 1-磷酸 (S1P)，由鞘氨醇激酶产生，调节未折叠线粒体的激活 蛋白质反应（UPRmt）。 UPRmt 对于维持线粒体蛋白稳态至关重要 对线粒体应激的反应，但其激活的分子机制尚不完全清楚 明白了。我的实验室使用秀丽隐杆线虫模型来研究鞘脂信号传导在 调节神经元功能和神经递质释放。我们最近发现了一个新颖的功能 唯一的鞘氨醇激酶同源物 SPHK-1，激活 UPRmt 并促进整个生物体 针对多种线粒体应激源的保护。我们发现 SPHK-1 与 线粒体并且这种关联受到任一细胞产生的线粒体应激的调节 自主地（在肠道中）或细胞非自主地（通过神经系统）。在这里我们寻求 揭示鞘脂信号传导过程中调节的细胞和分子机制 UPRmt，它如何激活 UPRmt 以及它如何影响线粒体稳态和存活 多细胞生物。在目标 1 中，我们确定线粒体应激的分子机制 调节 SPHK-1 的靶向和功能。在目标 2 中，我们确定神经内分泌信号如何调节 UPRmt 期间的鞘脂信号传导。在目标 3 中，我们确定了 UPRmt 期间 S1P 的细胞靶标 它们如何调节转录反应以确保适当的细胞稳态和面部存活 的压力。该提案将促进对线粒体鞘氨醇激酶如何发挥作用的机制的理解 在体内受到调节和发出信号，并将进一步了解激活的机制 普遍定期审议