Accelerating General Anesthetic Discovery and Mechanisms Research with Zebrafish
Accelerating General Anesthetic Discovery and Mechanisms Research with Zebrafish
批准号:
9983104
负责人:
STUART A FORMAN
金额:
$37.99万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-01 至 2021-07-31
关键词:
Academic Medical CentersAdrenergic ReceptorAffectAgeAmnesiaAnestheticsBiological AssayBostonCRISPR/Cas technologyClinicalComputer softwareDataData AnalysesDevelopmentDiseaseDrug KineticsDrug ScreeningDrug TargetingElectrophysiology (science)EquipmentFishesGene MutationGeneral AnesthesiaGeneral anesthetic drugsGeneticGlycine ReceptorsGoalsHCN1 geneHypnosisImmobilizationIntravenousIntravenous AnestheticsIon ChannelKnock-inKnock-outKnockout MiceLarvaLeadLearningLibrariesLinkMeasuresMediatingMedicineModelingModern MedicineModernizationMolecularMolecular StructureMolecular TargetMotionMutationN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNervous system structureNeurobiologyNeuronsPainPatient CarePatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPhenotypePlayProbabilityProceduresPropertyRattusReflex actionResearchResponse to stimulus physiologyRiskRoleSedation procedureSeriesSiteSprague-Dawley RatsStimulusStructureStructure-Activity RelationshipTadpolesTestingTransgenic OrganismsUniversitiesVariantVulnerable PopulationsXenopusZebrafishbasedrug mechanismexperimental analysisexperimental studyhypnoticimprovedinhibitor/antagonistintravenous administrationmolecular modelingmutantneurobiological mechanismnovelnovel strategiesnovel therapeuticsreceptorresponsescale upsedativeside effectsuccesstoolvoltage clamp
中文摘要
摘要:全身麻醉是现代程序医学的重要组成部分。我们迫切需要这样做
英文摘要
ABSTRACT: General anesthesia is essential for modern procedural medicine. There is a compelling need to
find superior alternatives to current sedative-hypnotics, which derive from a few drug classes identified before
1980, and also cause undesirable or harmful side effects, especially in vulnerable populations. To date,
strategies to discover new anesthetics are based on molecular models, mostly GABAA receptors, that are
targets for a few potent intravenous hypnotics. Our long-term goals are to identify new sedative-hypnotic
chemotypes that may improve patient care, while also advancing molecular and neurobiological research on
anesthetic mechanisms. We hypothesize that a wide variety of undiscovered potent sedative-hypnotic
chemotypes exists. These may modulate GABAA receptors through several known sites, or act through other
known or perhaps unknown mechanisms. Our novel strategy uses concurrent video motion analysis of up to
96 zebrafish larvae as a high-throughput un-biased stimulus-response test platform to accelerate discovery
and characterization of new potent sedative-hypnotics. Zebrafish larvae immersed in solutions of non-volatile
drugs rapidly establishes steady-state conditions for assessing pharmacodynamic effects. Combining this
approach with new transgenic zebrafish lines harboring mutations that alter or eliminate known and
suspected general anesthetic targets in the nervous system will also accelerate exploration of molecular
and neurobiological mechanisms. In Aim 1, we will use video analysis tools to assess both baseline motion
and photomotor response probability in up to 96 zebrafish larvae simultaneously. We have developed robust
experimental and data analysis approaches to both screen for new sedative-hypnotics and determine sedative
and hypnotic potencies (Aim 1a). We already have identified several potent active lead compounds in a drug
library from the Boston University Center for Medical Discovery (BUCMD). New active leads will also be tested
for activity/potency in both tadpoles and rats (Aim 1b). Collaborators at BUCMD will also synthesize structural
variants of selected lead compounds, enabling exploration of structure-activity relationships for sedation and
hypnosis in zebrafish, as illustrated in preliminary data (Aim 1c). In Aim 2, we will explore the molecular
mechanisms of new sedative-hypnotics using voltage-clamp electrophysiology in a panel of heterologously
expressed ion channels (GABAARs, GlyRs, NMDA-Rs, neuronal nAChRs, HCN1 and TREK-3) or
antipamezole antagonism of α2 adrenergic receptors (Aim 2a). Sedative-hypnotics that potentiate GABAARs,
will also be tested in a series of receptor mutants to assess selectivity for known subsites (Aim 2b). In Aim 3,
we will use CRISPR-Cas9 to create transgenic zebrafish lines for testing the roles of drug targets in sedation
and hypnosis. We will first create a panel of GABAAR subunit knock-out and knock-in lines (Aim 3a; β3 and δ
KOs are made). We will also make knockouts for HCN1 (already made), TREK-3, K2P and α2 AdRs (Aim 3b).
Sedative and hypnotic potencies of known and novel drugs will be compared in mutant vs. wild-type zebrafish.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Basic and Translational Research on General Anesthetics
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批准号:10395548
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项目类别:
-
资助金额:$70.04万
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财政年份:2021
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负责人:STUART A FORMAN
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依托单位:
Basic and Translational Research on General Anesthetics
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批准号:10206422
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项目类别:
-
资助金额:$50.76万
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财政年份:2021
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负责人:STUART A FORMAN
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依托单位:
Basic and Translational Research on General Anesthetics
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批准号:10599115
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项目类别:
-
资助金额:$70.04万
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财政年份:2021
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负责人:STUART A FORMAN
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依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:9975188
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项目类别:
-
资助金额:$34.06万
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财政年份:2010
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负责人:STUART A FORMAN
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依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:8775923
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项目类别:
-
资助金额:$34.75万
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财政年份:2010
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负责人:STUART A FORMAN
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依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:9312844
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项目类别:
-
资助金额:$33.59万
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财政年份:2010
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负责人:STUART A FORMAN
-
依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:8510665
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项目类别:
-
资助金额:$34.39万
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财政年份:2010
-
负责人:STUART A FORMAN
-
依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:8136477
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项目类别:
-
资助金额:$36.33万
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财政年份:2010
-
负责人:STUART A FORMAN
-
依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:8299577
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项目类别:
-
资助金额:$35.98万
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财政年份:2010
-
负责人:STUART A FORMAN
-
依托单位:
General Anesthetic Sites in GABA-A Receptor Subunit Interfacial Pockets
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批准号:7985708
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项目类别:
-
资助金额:$36.81万
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财政年份:2010
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负责人:STUART A FORMAN
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依托单位:
Project 3: Anesthetic Mechanisms on GABAA Receptors
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批准号:7777111
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项目类别:
-
资助金额:$28.44万
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财政年份:2009
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负责人:STUART A FORMAN
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依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:6868122
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项目类别:
-
资助金额:$30.31万
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财政年份:2003
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负责人:STUART A FORMAN
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依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:7578279
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项目类别:
-
资助金额:$14.44万
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财政年份:2003
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负责人:STUART A FORMAN
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依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:6701350
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项目类别:
-
资助金额:$30.32万
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财政年份:2003
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负责人:STUART A FORMAN
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依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:7028258
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项目类别:
-
资助金额:$29.6万
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财政年份:2003
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负责人:STUART A FORMAN
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依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:7194992
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项目类别:
-
资助金额:$28.73万
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财政年份:2003
-
负责人:STUART A FORMAN
-
依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:6556666
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项目类别:
-
资助金额:$29.16万
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财政年份:2003
-
负责人:STUART A FORMAN
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依托单位:
Volatile Anesthesia and the GABAA Receptor Gamma Subunit
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批准号:7369776
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项目类别:
-
资助金额:$28.73万
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财政年份:2003
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负责人:STUART A FORMAN
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依托单位:
ANESTHETIC MECHANISMS IN CLONED NICOTINIC AND GABA A RECEPTORS
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批准号:6564607
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项目类别:
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资助金额:$13.16万
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财政年份:2001
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负责人:STUART A FORMAN
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依托单位:
ANESTHETIC MECHANISMS IN CLONED NICOTINIC AND GABA A RECEPTORS
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批准号:6443401
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项目类别:
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资助金额:$13.16万
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财政年份:2000
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负责人:STUART A FORMAN
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依托单位:
海外基金