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Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism

Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism
开发化学蛋白质组学方法来破译 LRH-1(一种与肝脏代谢有关的核受体)的调控网络
批准号:
10249186
负责人:
Valentine Virginie Courouble
金额:
$2.09万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-01 至 2022-04-01
关键词:
AcetylationAffectAffinityAntibodiesAreaAtherosclerosisAutomobile DrivingBindingBiologyBiotinCancer EtiologyCardiovascular DiseasesCell NucleusCell physiologyCessation of lifeChemicalsCholesterol HomeostasisChromatinColon CarcinomaComplexConflict (Psychology)DNA BindingDiabetes MellitusDiagnosisDiseaseDisease PathwayEpitopesFosteringFunctional disorderGene ExpressionGenetic TranscriptionGrowthHealthHistone DeacetylaseImmunoprecipitationIndividualInvestigationKnowledgeLigand BindingLigandsLipidsLiverMalignant NeoplasmsMalignant neoplasm of liverMass Spectrum AnalysisMetabolicMetabolic DiseasesMetabolic syndromeMetabolismMethodologyMolecularMolecular ChaperonesMolecular TargetNR5A2 geneNon-Insulin-Dependent Diabetes MellitusNuclearNuclear ExportNuclear Localization SignalNuclear ReceptorsOligonucleotidesOutputOvaryPancreasPathway interactionsPhospholipidsPhysiologicalPhysiologyPlayPopulationPost-Translational Protein ProcessingPrimary carcinoma of the liver cellsProcessProtein IsoformsProteinsProteomicsReceptor SignalingRegulatory PathwayReportingResponse ElementsRiskRisk FactorsRoleSignal PathwaySignal TransductionSpecificitySteroid biosynthesisStreptavidinStructure-Activity RelationshipTissuesTractionZinc Fingersbasebile acid metabolismchemoproteomicsdesigninterestliver developmentliver metabolismmalignant stomach neoplasmnon-alcoholic fatty liver diseasenoveloverexpressionpolypeptidepreventreceptorreceptor functionscaffoldsmall moleculesmall molecule inhibitorsuccesstherapeutic targettooltool developmenttraffickingtranscription factor

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中文摘要
翻译
项目摘要/摘要:肝脏受体同源物-1 (Liver receptor homology -1, LRH-1; NR5A2)是一种磷脂敏感核
英文摘要
Project Summary/Abstract: Liver receptor homolog-1 (LRH-1; NR5A2) is a phospholipid-sensing nuclear receptor (NR) expressed predominantly in the liver, pancreas, and ovaries that plays an important role in metabolic physiologies and pathophysiologies. Specifically, it has been characterized to regulate bile acid metabolism, cholesterol homeostasis, and steroidogenesis, and in turn is involved in various disease states such as type 2 diabetes, atherosclerosis, nonalcoholic fatty liver disease as well as a multitude of cancers. These diseases are all risk factors for metabolic syndrome that affects nearly a third of the US population. This represents a significant health concern as individuals diagnosed with metabolic syndrome have increased risk for developing cardiovascular diseases as well as hepatocellular, gastric, and colon cancers; cancers that have been associated with overexpression of LRH-1. This suggests LRH-1 to be a promising therapeutic target for such metabolic diseases and cancers. However, a lack of a wholistic understanding of the receptors regulatory mechanism presents a significant limitation to the success of LRH-1 as a therapeutic target. Similar to other nuclear receptors, LRH-1's activity is tightly regulated via a multitude of pathways including cellular localization, ligand binding, DNA binding, post-translational modifications, and coregulator interactions. Cellular localization is central to these pathways as it determines the receptors milieu and thus available interacting partners. While, multiple nuclear localization signals and nuclear export signals have been identified to facilitate receptor shuttling in and out of the nucleus, there is no information regarding LRH-1 intranuclear trafficking, a key process that directly modulates DNA binding and transcriptional output. This propels the need to develop effective and specific tools to modulate LRH-1 localization and activity. While the use of chemical approaches to probe NRs in metabolism has increased over the years, the use of chemoproteomics in this area remains limited. Proteomic analysis of nuclear receptors remains problematic as they are relatively low abundant and tightly bound to chromatin. As such, there is a need for tools to probe and capture endogenous LRH-1 and LRH-1 transcriptional complexes. I propose the following specific aims to develop and employ LRH-1 specific chemoproteomic tools to elucidate the role of acetylation and a novel coregulator lamina associated polypeptide 2 (LAP2) in regulating LRH-1 intranuclear trafficking and signaling. In Aim 1, I will establish two LRH-1 specific probes to more efficiently modulate and/or capture LRH-1 and LRH-1 transcriptional complexes. These include a biotinylated LRH-1 response element oligo probe and SR1848, small molecule inhibitor of LRH-1 signaling. In Aim 2, I will identify LRH-1 acetylated residues and validate LAP2 isoforms as novel LRH-1 coregulators that coordinate to fine tune LRH-1 intranuclear trafficking and subsequent signaling. Elucidation of this regulatory pathway will directly enhance understanding of LRH-1 signaling driving hepatic cancer and other metabolic diseases.
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Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism
  • 批准号:
    10592215
  • 项目类别:
  • 资助金额:
    $1.21万
  • 财政年份:
    2020
  • 负责人:
    Valentine Virginie Courouble
  • 依托单位:
海外基金