High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
基本信息
- 批准号:10331230
- 负责人:
- 金额:$ 66.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcademiaAddressAmino AcidsAutomobile DrivingBiochemicalBiological AssayBlood VesselsBranched-Chain Amino AcidsCatabolismCell SurvivalCellsClinicalCoenzyme ACollaborationsDevelopmentDiabetes MellitusDiseaseDoseEndothelial CellsEndotheliumEnoyl-CoA HydrataseEnzymesEpidemiologyEvaluationEyeFatty AcidsFatty acid glycerol estersGoalsHumanIn VitroInsulinInsulin ResistanceLeadLinkLipidsMeasuresMetabolicModelingMolecularMorbidity - disease rateMusMuscleMuscle CellsMuscle FibersNational Institute of Diabetes and Digestive and Kidney DiseasesNon-Insulin-Dependent Diabetes MellitusOxidesPathway interactionsPlant RootsPrivate SectorProcessProductionRecording of previous eventsRespirationSafetySerumSkeletal MuscleSpecificityStructureTestingTextTherapeutic AgentsTissuesValidationValineWorkassay developmentbasecounterscreenefficacy testingepidemiology studyexperimental studyfatty acid transporthigh throughput screeningimaging agentin silicoin vivoin vivo Modelinterestmetabolomicsmortalitymouse modelnovelnovel therapeuticsparacrinepharmacokinetics and pharmacodynamicspre-clinicalpreventprospectiveresponsescreeningskeletalsmall moleculesuccesstraffickinguptakevirtual
项目摘要
PROJECT SUMMARY / ABSTRACT
Insulin resistance (IR) in skeletal muscle and other tissues is obligatory for the development of type 2 diabetes.
Excess accumulation of incompletely oxidized non-esterified fatty acids (FAs) in muscle cells, i.e., lipotoxicity,
is increasingly appreciated to underlie the development of IR. In parallel, branched chain amino acids (BCAAs)
have recently moved front and center in the field of diabetes, as unbiased metabolomic profiling in large
prospective epidemiological studies has shown that serum elevations of BCAAs predict IR and diabetes as
much as 20 years prior to clinical presentation. We have now uncovered a novel molecular pathway that links
these two observations. Active catabolism of the BCAA valine in skeletal muscle causes the paracrine
secretion of a metabolite, 3-hydroxyisobutyrate (3-HIB), which promotes entry of FAs into skeletal muscle, and
subsequent lipotoxicity.
The identification of this pathway provides a novel entry point for the potential treatment of insulin resistance,
orthogonal to most current insulin-based or insulin secretogenic therapies. The proposed project responds to
PA-16-374 (Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of
Interest to the NIDDK) and will identify lead-enabling small molecules that target this newly discovered
pathway. Aim 1 use in silico and high-throughput screening to identify molecules that block production of 3HIB.
Identified hits will be taken through a robust workflow of secondary counterscreens. In Aim 2, the molecules
identified in Aim 1 will be tested for efficacy and safety in intact cells. In Aim 3, validated hits from Aims 1 and 2
will first be submitted to in vivo pharmacokinetic and pharmacodynamic studies. Viable candidates will then be
tested for their ability to block lipid accumulation and insulin resistance in 3HIB-treated mice as well as in a pre-
clinical high-fat fed model of insulin resistance.
The proposed work represents a close collaboration between academia and a strong private sector team with
a long history of successes. We propose a novel and provocative hypothesis, and a previously unexplored
approach to understand and target lipotoxicity. Success would yield novel targets and potential lead
compounds for the development of new therapeutics that address the root of insulin resistance.
项目摘要/摘要
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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Zoltan P Arany其他文献
Zoltan P Arany的其他文献
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{{ truncateString('Zoltan P Arany', 18)}}的其他基金
Comprehensive quantification of fuel use in cold-induced thermogenesis in vivo
体内冷诱导生热过程中燃料使用的综合量化
- 批准号:
10637680 - 财政年份:2023
- 资助金额:
$ 66.13万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10343859 - 财政年份:2021
- 资助金额:
$ 66.13万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino Acids
保持肌肉中的脂肪——支链氨基酸的作用
- 批准号:
10186735 - 财政年份:2018
- 资助金额:
$ 66.13万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance
保持肌肉中的脂肪 - 支链氨基酸氨基酸在胰岛素抵抗中的作用
- 批准号:
10736605 - 财政年份:2018
- 资助金额:
$ 66.13万 - 项目类别:
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