Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi
PGRN 调节剂作为额颞叶痴呆新疗法的验证
基本信息
- 批准号:9674183
- 负责人:
- 金额:$ 81.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgingAllelesAlzheimer&aposs DiseaseBenefits and RisksBindingBiochemicalBiologicalBiological AssayBrainCRISPR/Cas technologyCardiovascular DiseasesCell physiologyCellsCellular AssayCellular MembraneCellular biologyChemicalsClinicalCollaborationsComplexCultured CellsDementiaDigestionDoseDrug KineticsDrug ScreeningEnhancersEpigenetic ProcessFamilial HypercholesterolemiaFrontotemporal DementiaFrontotemporal Lobar DegenerationsFunctional disorderFutureGRN geneGene ExpressionGene Expression ProfileGeneral HospitalsGenerationsGeneticGenetic TranscriptionGenomic approachGlycolipidsGlycosphingolipidsGolgi ApparatusHeterozygoteHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHomeostasisImpairmentIndividualInflammationInflammatoryInfusion proceduresInstitutionIsoxazolesKineticsKnock-outLaboratoriesLigandsLinkLipidsLysosomal Storage DiseasesLysosomesMassachusettsMeasuresMembrane LipidsMessenger RNAMetabolicMetabolismMethodsMonitorMusMutant Strains MiceNerve DegenerationNeurobiologyNeurodegenerative DisordersNeuronal Ceroid-LipofuscinosisNeuronsNuclear Hormone ReceptorsOrganellesPGRN genePharmaceutical ChemistryPharmaceutical PreparationsPhysiologicalProductionPropertyProteomeProteomicsResearchResolutionRiskRouteSamplingSeriesSpecificityStructure-Activity RelationshipSyndromeTechniquesTestingTherapeuticTissuesValidationbasecellular targetingchromatin modificationclinical translationcytokinedisorder riskdrug discoveryextracellularfunctional genomicsgene therapyin vivoin vivo evaluationinnovationmedical schoolsnovelnovel therapeuticspharmacodynamic biomarkerpre-clinicalpreclinical developmentpreclinical efficacyprogramspromoterresponsescreening programsmall moleculetheoriestranscriptometranscriptomics
项目摘要
Haploinsufficiency of the GRN gene encoding Progranulin (PGRN) is the genetic cause for a common form of
frontotemporal lobar degeneration (FTLD) giving rise to a distinctive frontotemporal dementia syndrome. It is
the second most common form of dementia after Alzheimer's disease and currently no effective cure exists for
either form of neurodegeneration. Complete lack of PGRN causes a form of neuronal ceroid lipofuscinosis
(NCL), a genetically heterogeneous form of lysosomal storage disease in which the digestion of cellular
membranes and glycosphingolipids is impaired, resulting in the accumulation of large misshaped lysosomes
especially in neurons. This discovery has shaped our current understanding of GRN haploinsufficiency as a
genetically distinct latent form of lysosomal dysfunction that accelerates the `normal' progressively diminishing
lysosomal capacity during aging. Lysosomal dysfunction syndromes are thought to induce the production of
inflammatory cytokines in part through the reduced generation of physiological lipid ligands for inflammation
suppressing nuclear hormone receptors, which further promotes neurodegeneration by increasing microglial
activation and synaptophagy. FTLD caused by GRN haploinsufficiency offers a unique therapeutic avenue
by increasing gene expression from the remaining functional allele. In theory, doubling of baseline GRN
expression should completely negate the risk for this form of FTLD in affected individuals. Our team has
developed a comprehensive small molecule discovery strategy that has led to the identification of several
chemically and mechanistically distinct classes of GRN transcriptional enhancers. The purpose of this project
is to investigate the biochemical and cell biological mechanisms through which these small molecules act on
the GRN gene and optimize their specificity and preclinical efficacy. This will be achieved by pursuing three
major aims: Aim 1 Prioritize and optimize PGRN enhancers for preclinical development based upon efficacy
and functional signatures from integrated ex vivo and in vivo studies; Aim 2 Determine the translational
potential of PGRN enhancing compounds by evaluating their ability to normalize the cellular and brain
transcriptome and lipidome; and Aim 3 Determine the translational potential of PGRN enhancing compounds
by investigating their effects on cellular membrane lipid composition and the lysosomal lipidome and proteome.
编码前颗粒蛋白(PGRN)的GRN基因单倍性不足是一种常见形式的糖尿病的遗传原因
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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STEPHEN J HAGGARTY其他文献
STEPHEN J HAGGARTY的其他文献
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$ 81.48万 - 项目类别:
Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi
PGRN 调节剂作为额颞叶痴呆新疗法的验证
- 批准号:
10480905 - 财政年份:2018
- 资助金额:
$ 81.48万 - 项目类别:
Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi
PGRN 调节剂作为额颞叶痴呆新疗法的验证
- 批准号:
10237945 - 财政年份:2018
- 资助金额:
$ 81.48万 - 项目类别:
Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi
PGRN 调节剂作为额颞叶痴呆新疗法的验证
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9791027 - 财政年份:2018
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Epigenetic Radiotracers for PET Imaging: Isoform-SelectiveHDAC Probes
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