课题基金 / 基金详情

A Novel Approach to Restore Epithelial Barrier Homeostasis to Treat Inflammatory Bowel Disease

A Novel Approach to Restore Epithelial Barrier Homeostasis to Treat Inflammatory Bowel Disease
恢复上皮屏障稳态以治疗炎症性肠病的新方法
批准号:
10484275
负责人:
W Vallen Graham
金额:
$79.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-15 至 2022-11-15
关键词:
ActomyosinAcuteAcute DiseaseAdverse effectsAffinityAttenuatedAwardBindingBiochemicalBiopsyCeliac DiseaseCell Adhesion MoleculesCell LineCellular AssayChronicChronic DiseaseClinicalColitisCrystallizationDataDevelopmentDiseaseDoseDrug KineticsEnteralEnterocolitisEpithelialEpithelial CellsEvaluationFood HypersensitivityFormulationFoundationsFunctional disorderGastrointestinal DiseasesHealthHomeostasisHumanImmuneImmunoglobulinsImmunomodulatorsImmunosuppressionImmunosuppressive AgentsInflammationInflammatoryInflammatory Bowel DiseasesInterleukin-10Intestinal DiseasesIntestinesKnock-outKnockout MiceLeadLibrariesLightMediatingMedicineModelingMucous MembraneMusMuscle ContractionMyosin Alkali Light ChainsMyosin Light Chain KinaseMyosin Type IINatureOutcomePathologicPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPhasePhosphorylationProtein IsoformsRNA SplicingRegulationReportingRiskRoleSmall Business Innovation Research GrantSmooth MuscleStimulusStructureStructure-Activity RelationshipSystemic diseaseT cell therapyT-LymphocyteTNF geneTherapeuticTight JunctionsTissuesToxic effectToxicity TestsVariantWaste ProductsWaterWorkbasecandidate selectionclinical applicationcytokinedosageefficacy studyepithelial woundexperiencegraft vs host diseaseimmune activationimprovedin vivointestinal barrierintestinal epitheliumlead candidatelead optimizationmouse modelnovelnovel strategiesnutrient absorptionpathogenphase 2 studypreservationpreventprogramsrecruitrepairedrestorationscaffoldscreeningsmall moleculetherapeutic targettoolwound healing

项目摘要

项目成果

W Vallen Graham的其他基金

相似基金

相关文献

中文摘要
翻译
总结
英文摘要
SUMMARY Intestinal barrier function is compromised in enteric and systemic diseases, including infectious enterocolitis, food allergy, celiac disease, graft versus host disease (GvHD), and inflammatory bowel disease (IBD). The co-founders of Thelium Therapeutics discovered the central role of myosin light chain kinase (MLCK) in barrier regulation and demonstrated that targeted intestinal epithelial MLCK inhibition limits experimental IBD and GvHD. Unfortunately, severe toxicities associated with barrier-independent MLCK functions in epithelia and other tissues, e.g., smooth muscle, preclude therapeutic targeting of MLCK enzymatic activity. We recently reported (Graham et al., Nature Medicine, 2019) that a specific MLCK splice variant, MLCK1, is central to barrier regulation and depends on interactions mediated by immunoglobulin-cell adhesion molecule domain 3 (IgCAM3). We solved the IgCAM3 crystal structure, identified a drug binding pocket unique to IgCAM3, and screened a library of ~140,000 drug-like molecules. Our tool compound, Divertin, bound IgCAM3, prevented cytokine-induced MLCK1 recruitment, myosin II regulatory light chain phosphorylation, and barrier dysfunction. Critically, Divertin did not inhibit MLCK enzymatic function, epithelial wound healing, or smooth muscle contraction, and in vivo toxicity studies failed to identify adverse effects. Divertin prevented acute TNF-induced barrier loss in vivo (mice) and ex vivo (human intestinal biopsies), and restored immune-mediated barrier loss in vivo (IL-10 knockout mice). Finally, Divertin delayed onset and prevented progression of experimental immune-mediated (T cell transfer) IBD, as indicated by barrier preservation and restoration, reduced mucosal immune activation, and enhanced survival. In a Phase I SBIR, we advanced this program through the discovery of hit compounds with improved activities. Hit compounds were discovered through a rigorous rank order screening funnel to identify compounds with suitable MLCK1 binding affinities, efficacy in preserving and restoring epithelial barrier function, and absence of enzymatic inhibitory activity. In this Phase II proposal, these hit compounds will be optimized with iterative structure activity relationship studies and tested for toxicity and efficacy in mouse models of IBD. This work will facilitate IND-enabling studies for a first-in-class and best-in-class barrier-restorative therapy to manage gastrointestinal and systemic diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
A Novel Approach to Restore Epithelial Barrier Homeostasis to Treat Inflammatory Bowel Disease
  • 批准号:
    9909608
  • 项目类别:
  • 资助金额:
    $22.43万
  • 财政年份:
    2019
  • 负责人:
    W Vallen Graham
  • 依托单位:
海外基金