Inhibition of ALDH1A1 for the treatment of obesity
抑制 ALDH1A1 治疗肥胖
基本信息
- 批准号:9517371
- 负责人:
- 金额:$ 31.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-22 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:ALDH1A2 geneAdipocytesAdipose tissueAdultAdverse effectsAffectAmericanAnabolismAnimalsAttenuatedBiological AssayBody Weight decreasedBody mass indexCharacteristicsComorbidityComputer SimulationConsumptionContraceptive UsageCrystallizationDataDevelopmentDietDrug KineticsEnergy MetabolismEnzymesEthanol toxicityExcretory functionGene ExpressionGluconeogenesisGoalsHigh Fat DietHigh PrevalenceHomeostasisHumanImmunityIn VitroInflammationIsoenzymesKnock-outLeadLipolysisLiverMale Contraceptive AgentsMetabolicMetabolismMolecular ModelsMusMuscleObese MiceObesityOxidative PhosphorylationPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacological TreatmentPharmacologyPhenotypeProcessPublic HealthRegulationReproductionResearchRetinalRetinoidsRoleSafetySpecificitySpermatogenesisStructure-Activity RelationshipTestingTestisThermogenesisTissue DifferentiationTissuesToxic effectTretinoinTriglyceridesUnited StatesVisceralWeightWeight GainWorkaldehyde dehydrogenasesattenuationbasedesignefficacy testingenzyme structureglucose metabolismhuman tissueimprovedinhibitor/antagonistlipid biosynthesislipid metabolismmolecular modelingmouse modelnovelobesity treatmentpharmacophorescreeningsmall moleculesmall molecule inhibitorsubcutaneous
项目摘要
PROJECT SUMMARY
Our long-term goal is to develop safe and effective drugs to treat obesity. The proposed studies are aimed at
validating a new target, ALDH1A1, the major enzyme involved in generating retinoic acid (RA) in adipose
tissues, for the treatment of obesity. RA is synthesized by three main aldehyde dehydrogenases, ALDH1A1,
ALDH1A2, and ALDH1A3 that are expressed in temporally and spatially distinctive patterns and are involved in
processes including development, reproduction and immunity. RA also regulates expression of genes involved
in adipose tissue differentiation as well as glucose and lipid metabolism. During our efforts to develop male
contraceptives using small molecules that reduce RA synthesis in the testes, we observed that mice treated
with WIN 18,446, a pan-inhibitor of ALDH1A isozymes, had lower body weight gain due to a decrease in
adipose tissue mass. This attenuated weight gain was reversed by co-treatment with RA, suggesting that
ALDH1A inhibition (RA reduction) could be used for weight regulation. Thus, we tested the efficacy of RA
synthesis inhibition using a murine model of diet-induced obesity and found that WIN 18,446 is effective in
attenuating weight gain despite the animals’ continued consumption of a high fat diet. Others have
demonstrated that the absence of the RA synthesizing enzyme, Aldh1a1, alters energy metabolism in liver and
adipose tissues due to changes in tissue retinoid levels (RA and retinal) and thus, protecting mice against diet-
induced obesity. We hypothesize that pharmacological inhibition of RA biosynthesis by inactivating
ALDH1A1 is a novel target for the treatment of obesity. To test this, in Specific Aim 1, we will evaluate
efficacy and toxicity of WIN 18,446 as an obesity treatment and will additionally determine potential
mechanisms, including alterations in energy metabolism in liver, adipose tissues and muscles, increased
thermogenesis in adipose tissue and effects on adipogenesis. Retinoid concentrations and the expression
pattern of the three RA synthesis enzymes will also be examined in human visceral and subcutaneous adipose
tissues to determine whether differences in RA homeostasis (retinal and RA concentrations) correlate with
body mass index in humans. Although WIN 18,446 is a promising compound for weight regulation, its
inhibition of all three RA synthesis enzymes and other ALDH enzymes has been shown to cause unwanted
side effects such as inhibition of spermatogenesis and alcohol toxicity. In Specific Aim 2, we propose to
develop ALDH1A1 specific inhibitors to treat obesity, minimizing the potential side effects associated with
complete inhibition of retinoic acid synthesis. In Specific Aim 3, we will test the efficacy of our new ALDH1A1-
specific inhibitors for the treatment of obesity in mice. The proposed studies will identify a novel target to treat
obesity with the potential to improve metabolic abnormalities associated with obesity.
项目总结
项目成果
期刊论文数量(0)
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{{ truncateString('JISUN PAIK', 18)}}的其他基金
Validation of ALDH1A1 as a target for the treatment of obesity: effects of ALDH1A1 inhibition on energy metabolism
验证 ALDH1A1 作为肥胖治疗靶点:抑制 ALDH1A1 对能量代谢的影响
- 批准号:
10681349 - 财政年份:2022
- 资助金额:
$ 31.1万 - 项目类别:
Validation of ALDH1A1 as a target for the treatment of obesity: effects of ALDH1A1 inhibition on energy metabolism
验证 ALDH1A1 作为肥胖治疗靶点:抑制 ALDH1A1 对能量代谢的影响
- 批准号:
10443471 - 财政年份:2022
- 资助金额:
$ 31.1万 - 项目类别:
Modernization of a Shared-use Gnotobiotic Animal Core
共享使用知生动物核心的现代化
- 批准号:
10532456 - 财政年份:2022
- 资助金额:
$ 31.1万 - 项目类别:
Regulation of vitamin A synthesis from carotenoids
类胡萝卜素合成维生素 A 的调节
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6885742 - 财政年份:2004
- 资助金额:
$ 31.1万 - 项目类别:
Regulation of vitamin A synthesis from carotenoids
类胡萝卜素合成维生素 A 的调节
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7025054 - 财政年份:2004
- 资助金额:
$ 31.1万 - 项目类别:
Regulation of vitamin A synthesis from carotenoids
类胡萝卜素合成维生素 A 的调节
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6704470 - 财政年份:2004
- 资助金额:
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Regulation of vitamin A synthesis from carotenoids
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- 资助金额:
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