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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：
10683149
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/10683149
关键词：
Behavioral Biological Biological Process Caenorhabditis elegans Cardiovascular Diseases Cell physiology Cells Cellular Stress Complex Development Disease Ensure Experimental Designs Fibroblast Growth Factor Generations Genetic Genetic Transcription Goals Homeostasis Inflammation Intestines Kinetics Laboratories Lipids Malignant Neoplasms Mediator Mitochondria Mitochondrial Proteins Modeling Molecular Nervous System Neurodegenerative Disorders Neurons Neuropeptides Neurosecretory Systems Organism Orthologous Gene Outer Mitochondrial Membrane Physiological Processes Production Protein Isoforms Proteins Regulation Research Role Signal Pathway Signal Transduction Sphingolipids Sphingosine Stress Stroke Testing cellular targeting gene function in vivo mitochondrial membrane model organism 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.

项目总结