Functional Characterization of Diacylglycerol Lipases in Mammalian Physiology
Functional Characterization of Diacylglycerol Lipases in Mammalian Physiology
批准号:
9109601
负责人:
Ku-Lung Hsu
金额:
$24.65万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-07-15 至 2018-06-30
关键词:
2-arachidonylglycerolAddressAdipose tissueAdoptive Cell TransfersAdverse effectsAnabolismAnimal ModelAnimalsAntidiabetic DrugsBehavioralBiochemicalBiological AssayBody TemperatureBody WeightCNR1 geneCNR2 geneCaloriesCarbon DioxideChemicalsChemotaxisChronicClinicalDevelopmentDietDiglyceridesDiseaseEatingEicosanoidsEndocannabinoidsEnergy MetabolismEnzyme Inhibitor DrugsEnzyme InhibitorsEnzymesEthanolaminesFatty acid glycerol estersFlow CytometryG-Protein-Coupled ReceptorsGeneticGoalsHeatingHigh Fat DietHomeostasisHydrolaseInflammationInflammatoryInflammatory ResponseK-Series Research Career ProgramsKnock-outKnockout MiceLabelLeadLipidsMarijuanaMeasurementMeasuresMediatingMentorsMetabolicMetabolic DiseasesMetabolic PathwayMetabolic syndromeMetabolismMonitorMonoacylglycerol LipasesMusNeuraxisNeuronsNon-Insulin-Dependent Diabetes MellitusObesityObesity associated diseaseOrganismOxygenPainPathway interactionsPeripheralPeritoneal MacrophagesPharmaceutical PreparationsPhasePhenotypePhysiologicalPhysiologyPre-Clinical ModelProcessProductionProtein IsoformsProteomicsRegulationSerine HydrolaseSignal PathwaySignal TransductionSignaling MoleculeSiteSynthesis ChemistrySystemTestingTetrahydrocannabinolTherapeutic EffectTissuesTrainingTransgenic MiceTransmembrane Domainabstractinganandamidearachidonatebalance testingchemoproteomicsdiabeticendogenous cannabinoid systemenergy balancefeedingin vivoinhibitor/antagonistinnovationinsightinsulin sensitivitylipoprotein lipasemacrophagemetabolic phenotypemetabolomicsmonocytemouse modelnovel therapeuticsoverexpressionpreventrespiratorysmall molecule inhibitor
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
The overall goal of this K99/R00 career development award proposal is to integrate innovate chemical probes,
including in vivo-active small-molecule inhibitors and specialized chemoproteomic assays, with well-
established genetic knockout and behavioral mouse models to obtain a global view of the pathophysiological
consequence of disrupting 2-arachidonoylglycerol (2-AG) biosynthesis in mouse models of obesity and
inflammation. The endogenous cannabinoid (endocannabinoid) 2-AG is a lipid transmitter that activates the G-
protein-coupled receptors CB1 and CB2, which are also targets for the psychoactive ingredient in marijuana,
∆9-tetrahydrocannabinol. The importance of the endocannabinoid system in obesity-associated metabolic
disorders is highlighted by the clinical activity of CB1 antagonists as anti-obesity and anti-diabetic drugs.
Complementary studies in preclinical models have since shown that many of the beneficial effects are due to
blocking CB1 receptors at peripheral sites. These studies highlight the need for a deeper understanding of the
central and/or peripheral contributions of the endocannabinoid system in regulating energy homeostasis as
well as obesity-related disease states. 2-AG biosynthesis in vivo is differentially regulated by two sequence-
related enzymes, diacylglycerol lipase-α and β (DAGLα and DAGLβ, respectively), providing an experimental
(and, eventually translational) opportunity to uncouple central and peripheral endocannabinoid signaling
through selective inactivation of DAGL isoforms. This proposal will test the hypothesis that DAGLα and
DAGLβ biosynthesize 2-AG involved in energy homeostasis and perform complementary functions in energy
balance through regulation of CB1-dependent signaling at anatomically-distinct sites. The specific aims are to
1) measure energy homeostasis parameters and body mass composition in vivo in DAGL-disrupted mice 2)
measure adipose tissue macrophage accumulation in DAGL-disrupted mice and 3) Determine the
physiological effects of inactivating DAGLs in the development and progression of metabolic syndrome. Our
preliminary studies show that DAGLα display a lean phenotype despite increased food intake, providing
evidence of altered energy balance upon central and/or peripheral disruption of 2-AG biosynthesis. Our
preliminary studies also show the feasibility of using DAGL-selective inhibitors to uncouple central and
peripheral 2-AG signaling pathways in vivo.
The candidate aims to combine previous training in chemoproteomics, synthetic chemistry, and quantitative
proteomics and metabolomics with new mentored training in mouse models of metabolism and inflammation
including non-invasive measurements of metabolic parameters governing energy homeostasis and body mass
composition as well as in vivo tracking of adipose tissue macrophage accumulation using adoptive cell transfer
and flow cytometry.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Chemical proteomic investigation of lipid kinase specificity and druggability
-
批准号:10660099
-
项目类别:
-
资助金额:$39.13万
-
财政年份:2023
-
负责人:Ku-Lung Hsu
-
依托单位:
Defining and targeting substrate specificity of protein tyrosine phosphatases
-
批准号:10341499
-
项目类别:
-
资助金额:$34.37万
-
财政年份:2022
-
负责人:Ku-Lung Hsu
-
依托单位:
Defining and targeting substrate specificity of protein tyrosine phosphatases
-
批准号:10538607
-
项目类别:
-
资助金额:$19.39万
-
财政年份:2022
-
负责人:Ku-Lung Hsu
-
依托单位:
Defining and targeting substrate specificity of protein tyrosine phosphatases
-
批准号:10580475
-
项目类别:
-
资助金额:$24.99万
-
财政年份:2022
-
负责人:Ku-Lung Hsu
-
依托单位:
Endocannabinoid Biosynthesis in Inflammation and Pain
-
批准号:9398439
-
项目类别:
-
资助金额:$39.14万
-
财政年份:2017
-
负责人:Ku-Lung Hsu
-
依托单位:
Endocannabinoid Biosynthesis in Inflammation and Pain
-
批准号:10400420
-
项目类别:
-
资助金额:$0.99万
-
财政年份:2017
-
负责人:Ku-Lung Hsu
-
依托单位:
Endocannabinoid Biosynthesis in Inflammation and Pain
-
批准号:9980632
-
项目类别:
-
资助金额:$4.28万
-
财政年份:2017
-
负责人:Ku-Lung Hsu
-
依托单位:
Endocannabinoid Biosynthesis in Inflammation and Pain
-
批准号:10198879
-
项目类别:
-
资助金额:$38.77万
-
财政年份:2017
-
负责人:Ku-Lung Hsu
-
依托单位:
Functional Characterization of Diacylglycerol Lipases in Mammalian Physiology
-
批准号:8701001
-
项目类别:
-
资助金额:$12.83万
-
财政年份:2014
-
负责人:Ku-Lung Hsu
-
依托单位:
海外基金