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.
编码颗粒蛋白前体(PGRN)的GRN基因的单倍不足是一种常见形式的
额颞叶变性(FTLD)引起一种独特的额颞叶痴呆综合征。是
老年痴呆症是仅次于阿尔茨海默氏病的第二种最常见的痴呆症,目前还没有有效的治疗方法。
任何一种形式的神经退化PGRN的完全缺乏导致一种形式的神经元蜡样脂褐质沉积症
(NCL),一种遗传异质性形式的溶酶体储存病,其中细胞的消化
膜和鞘糖脂受损,导致大的变形溶酶体积聚
尤其是神经元。这一发现塑造了我们目前对GRN单倍不足的理解,
一种遗传上不同的潜在形式的溶酶体功能障碍,加速了“正常”的逐渐减少
衰老过程中的溶酶体能力。溶酶体功能障碍综合征被认为是诱导产生
炎性细胞因子部分通过减少炎症的生理脂质配体的产生
抑制核激素受体,通过增加小胶质细胞,进一步促进神经变性,
激活和突触吞噬。由GRN单倍不足引起的FTLD提供了独特的治疗途径
通过增加剩余功能等位基因的基因表达。从理论上讲,
表达应该完全否定这种形式的FTLD在受影响的个人的风险。我们的团队已被
开发了一种全面的小分子发现策略,
化学上和机械上不同类别的GRN转录增强子。这个项目的目的
是研究这些小分子作用于细胞的生化和细胞生物学机制,
GRN基因并优化其特异性和临床前功效。这将通过追求三个
主要目的:目的1根据疗效优先考虑和优化PGRN增强剂用于临床前开发
和功能特征;目的2确定翻译的
通过评价PGRN增强化合物使细胞和脑正常化的能力来评价它们的潜力
目的3确定PGRN增强化合物的翻译潜力
通过研究它们对细胞膜脂质组成和溶酶体脂质组和蛋白质组的影响。
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的其他文献
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{{ truncateString('STEPHEN J HAGGARTY', 18)}}的其他基金
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结节性硬化症患者 iPSC 衍生的 NPC 和 NCC 作为人体模型系统来识别新靶点
- 批准号:
10408151 - 财政年份:2019
- 资助金额:
$ 81.48万 - 项目类别:
Tuberous Sclerosis Complex Patients iPSC-derived NPCs and NCCs as Human Model Systems to Identify Novel Targets
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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
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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
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10237945 - 财政年份:2018
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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
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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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