Sphingolipid signaling in mitochondrial surveillance

线粒体监测中的鞘脂信号传导

基本信息

批准号：
10017351
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
项目类别：
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/10017351
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

项目摘要

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.

项目摘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。长期拟议的研究的目标是确定鞘氨酸的细胞和分子机制由鞘氨醇激酶生成的1院（S1P）调节线粒体展开的激活蛋白质反应（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，但是其激活的分子机制并不完全理解。我的实验室使用秀丽隐杆线虫模型来研究鞘脂信号的作用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激活UPRMT和促进生物的唯一鞘氨醇激酶直系同源物SPHK-1 响应各种线粒体应激源的保护。我们发现SPHK-1与线粒体，该关联受到线粒体应力的调节自主（在肠道中）或非自主（通过神经系统）。我们在这里寻求揭示在调节过程中调节鞘脂信号传导的细胞和分子机制 UPRMT，它如何激活UPRMT及其如何影响线粒体稳态和生存多细胞生物。在AIM 1中，我们确定了线粒体应力的分子机制调节SPHK-1靶向和功能。在AIM 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AIM 3中，我们在UPRMT期间确定了S1P的细胞靶标它们如何调节转录反应以确保正确的细胞稳态和面部生存压力。该建议将提高对线粒体鞘氨醇激酶的理解受调节和体内信号，并将进一步了解 UPRMT。