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:
- 金额:$ 36.09万
- 依托单位:
- 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:
- 关键词:BehavioralBiologicalBiological ProcessCaenorhabditis elegansCardiovascular DiseasesCell physiologyCellsCellular StressComplexDevelopmentDiseaseEnsureExperimental DesignsFibroblast Growth FactorGenerationsGeneticGenetic TranscriptionGoalsHomeostasisInflammationIntestinesKineticsLaboratoriesLipidsMalignant NeoplasmsMediatorMitochondriaMitochondrial ProteinsModelingMolecularNervous SystemNeurodegenerative DisordersNeuronsNeuropeptidesNeurosecretory SystemsOrganismOrthologous GeneOuter Mitochondrial MembranePhysiological ProcessesProductionProtein IsoformsProteinsRegulationResearchRoleSignal PathwaySignal TransductionSphingolipidsSphingosineStressStrokeTestingcellular targetinggene functionin vivomitochondrial membranemodel organismneurotransmitter releasenovelprogramsprotective effectprotein functionproteostasisrecruitresponsesphingosine 1-phosphatesphingosine kinasestressor
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变性疾病以及中风有关。长期
这项研究的目的是确定神经鞘氨醇-
1-由鞘氨醇激酶产生的磷酸盐(S1 P)调节线粒体未折叠的
蛋白质反应(UPRmt)。UPRmt对于维持线粒体蛋白质稳态是至关重要的,
线粒体应激反应,但其激活的分子机制并不完全
明白我的实验室用的是C型。elegans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的功能,
唯一的鞘氨醇激酶直系同源物SPHK-1在激活UPRmt和促进生物体范围内的
保护,以应对广泛的线粒体应激。我们发现SPHK-1与
线粒体和这种协会是由线粒体压力产生的细胞调节
自主地(在肠中)或细胞非自主地(通过神经系统)。在这里,我们寻求
揭示细胞和分子机制,其中鞘脂信号调节过程中,
UPRmt,它如何激活UPRmt以及它如何影响线粒体稳态和生存,
多细胞生物在目标1中,我们确定了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
在UPRmt期间的鞘脂信号传导。在目标3中,我们确定了UPRmt期间S1 P的细胞靶点,
它们如何调节转录反应,以确保适当的细胞稳态和生存,
压力这一建议将促进对线粒体鞘氨醇激酶
是调节和信号在体内,并将进一步了解潜在的激活机制,
UPRmt。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('DEREK SIEBURTH', 18)}}的其他基金
Sphingolipid signaling in mitochondrial surveillance
线粒体监测中的鞘脂信号传导
- 批准号:
10468858 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
Sphingolipid signaling in mitochondrial surveillance
线粒体监测中的鞘脂信号传导
- 批准号:
10017351 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
Sphingolipid signaling in mitochondrial surveillance
线粒体监测中的鞘脂信号传导
- 批准号:
10240608 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
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