Novel Regulation of Receptor Tyrosine Kinases by ASM (Acidic Sphingomyelinase)
ASM(酸性鞘磷脂酶)对受体酪氨酸激酶的新调控
基本信息
- 批准号:9232921
- 负责人:
- 金额:$ 42.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-15 至 2020-05-30
- 项目状态:已结题
- 来源:
- 关键词:3 year oldAblationAcidsApoptosisBacterial InfectionsBiochemicalBrainCaenorhabditis elegansCancer Cell GrowthCell Signaling ProcessCell SurvivalCell membraneCell surfaceCellsCeramidesCerebellumCessation of lifeCholesterolClassical Niemann-Pick DiseaseComplexDeteriorationDiseaseDockingDrug resistanceEndocytosisEndosomesEnzymesExocytosisFamilyGenesGenetic ModelsGlycosphingolipidsGolgi ApparatusGrowthHomologous GeneHumanHydrolysisImageInheritedInsulin-Like-Growth Factor I ReceptorIntegral Membrane ProteinIslandLateralLeadLinkLipid BilayersLipidsLiverLungLysosomesMalignant NeoplasmsMammalian CellMediatingMembraneMembrane LipidsMembrane MicrodomainsMembrane ProteinsMetabolismMolecularMonitorMovementMutationNerve DegenerationNeurologicNeuronsNiemann-Pick DiseasesOrganellesPathway interactionsPatientsPhenotypePhospholipidsPhysiologicalPick Disease of the BrainPreventionProductionProtein DynamicsProteinsReceptor Protein-Tyrosine KinasesReceptor SignalingRegulationRoleSeaSignal PathwaySignal TransductionSignaling MoleculeSiteSphingolipidsSphingomyelinase Deficiency DiseasesSphingomyelinsSpleenStimulusStressStructureSurfaceSystemTNFRSF6 geneTailTestingTherapeuticTimeTransmembrane DomainTyrosineUltraviolet Raysacid sphingomyelinaseacidic sphingomyelinasebasebiophysical propertiescancer cellearly childhoodfunctional genomicshuman diseaseinsightlive cell imagingloss of functionloss of function mutationmeetingsmutantneuron lossnew therapeutic targetnovelphysical propertyprotein protein interactionprotein structure functionreceptorresponsesignal processingsrc-Family Kinases
项目摘要
Project Summary
We propose that ASM (acid sphingomylinase) is a critical regulator of RTKs (receptor tyrosine kinases), and
that ASM can serve as a novel therapeutic target for various cancers, including gliomablastoma multiforme
(GBM). Also as loss of function of ASM may cause the severe neuron degeneration phenotype in the rare
familial Niemann Pick Disease, type A, our studies may provide molecular insights into this disease.
The plasma membrane is a lipid bilayer composed primarily of phospholipids, as well as sphingomyelins,
cholesterol, glycosphingolipids and other less abundant lipid molecules such as ceremides. The composition of
the plasma membrane lipids is dynamically regulated and undergoes rapid exchanges with intracellular
organelles such as Golgi, endosomes and lysosomes through secretion, exocytosis and endocytosis. For many
transmembrane and membrane-associated proteins, including RTKs, specific interaction with various lipid
molecules in the plasma membrane is an integral part of regulation to maintain their protein structure and
function. However, the mechanisms by which specific lipid molecules regulate the dynamic activities of RTKs
and other transmembrane or membrane-associated proteins are not well characterized. In this application, we
propose to investigate the roles of ASM (also called SMPD1) in regulating the RTK-mediated cell signaling
processes.
We have recently found that the levels of ASM (acidic sphinomyelinase) are highly elevated in GBM and our
studies reveal that ASM is required for the activation of multiple RTKs. ASM is an enzyme involved in
sphingolipid metabolism that hydrolyzes sphingomyelin to produce ceramide. Ceramide, with a biophysical
property of self-association, is involved in establishing a lipid microenvironment that promotes protein-protein
interactions. Mutations of human ASM gene cause Niemman-Pick disease, type A, an inherited disease that
induces massive loss of Purkinje neurons in the cerebellum and patients usually die by 2 or 3 years of ages, but
the underlying molecular mechanism of ASM deficiency for the disease remains unresolved.
In this application, we will investigate the mechanism by which ASM regulates the RTK signaling pathway, by
following specific aims:
Specific aim 1: To determine how ASM regulates the activation RTK receptor proteins.
Specific aim 2: To investigate the involvement of ASM sphinomyelinase activity in RTK signaling.
Specific aim 3: To examine whether ASM regulates RTK signaling at multiple levels.
As co-activation of RTKs is critically important in GBM and in a multitude of human disorders and diseases,
elucidation of this new regulatory mechanism may provide novel targets for prevention and therapeutic
treatment. Our studies should also provide molecular underpinning how loss-of-function of ASM causes neuron
degeneration in the human diseases such as Niemman-Pick disease, type A.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('HONG SUN', 18)}}的其他基金
Novel Regulation of the Activation and Assembly of the Heterimeric Receptor Tyrosine Kinase Complexes for Cell Signaling
细胞信号转导异聚受体酪氨酸激酶复合物的激活和组装的新调控
- 批准号:
10046499 - 财政年份:2016
- 资助金额:
$ 42.8万 - 项目类别:
PTEN TUMOR SUPPRESSOR AND CELL CYCLE REGULATION
PTEN 肿瘤抑制剂和细胞周期调节
- 批准号:
6513335 - 财政年份:1999
- 资助金额:
$ 42.8万 - 项目类别:
PTEN TUMOR SUPPRESSOR AND CELL CYCLE REGULATION
PTEN 肿瘤抑制剂和细胞周期调节
- 批准号:
6633295 - 财政年份:1999
- 资助金额:
$ 42.8万 - 项目类别:
PTEN TUMOR SUPPRESSOR AND CELL CYCLE REGULATION
PTEN 肿瘤抑制剂和细胞周期调节
- 批准号:
6376738 - 财政年份:1999
- 资助金额:
$ 42.8万 - 项目类别:
PTEN TUMOR SUPPRESSOR AND CELL CYCLE REGULATION
PTEN 肿瘤抑制剂和细胞周期调节
- 批准号:
2909850 - 财政年份:1999
- 资助金额:
$ 42.8万 - 项目类别:
PTEN TUMOR SUPPRESSOR AND CELL CYCLE REGULATION
PTEN 肿瘤抑制剂和细胞周期调节
- 批准号:
6173631 - 财政年份:1999
- 资助金额:
$ 42.8万 - 项目类别:
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