Targeting neuroinflammation in AD with novel CX3CR1 agonists
使用新型 CX3CR1 激动剂靶向 AD 中的神经炎症
基本信息
- 批准号:10158381
- 负责人:
- 金额:$ 67.71万
- 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
- 起止时间:2019-05-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1AddressAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease therapyAminoquinolinesAmyloid beta-ProteinAmyloid depositionAnimal Disease ModelsAnimal ModelAnimalsAnti-Inflammatory AgentsAtrophicAutopsyBehavioralBinding ProteinsBioavailableBiochemicalBiological AssayBiological MarkersBrainCX3CL1 geneCatalogsCharacteristicsChemicalsChemistryDataDementiaDepositionDevelopmentDiseaseDisease ProgressionDisease modelDoseDrug KineticsEnsureFractalkineFunding OpportunitiesGoalsGrowth FactorHealthHumanImpaired cognitionInflammationInflammatoryInnate Immune SystemLeadMaximum Tolerated DoseMeasuresMediatingMedicalMembraneMicrogliaMolecularMusNerve DegenerationNeurodegenerative DisordersNeuronsOralOutcome MeasurePTPRC geneParkinson DiseasePathologicPathologyPathway interactionsPenetrationPeptidesPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhenotypePlasmaPlayPropertyProteinsProteomicsResistanceResourcesRodentRoleRouteSeriesSignal TransductionSolubilityTNF geneTauopathiesTestingTherapeuticTissuesTransgenic MiceWorkanalogcandidate markercerebral atrophychemokinedrug discoveryeffective therapyefficacy studyextracellularfractalkine receptorhigh throughput screeningimprovedin vitro Bioassayin vivolead optimizationmeetingsmouse modelmutantnervous system disorderneuroinflammationneuron lossnew therapeutic targetnovelnovel therapeuticsoverexpressionpre-clinicalpreclinical studyreceptorscaffoldsmall moleculesuccesstargeted treatmenttau Proteinstau phosphorylationtooltranscriptome sequencing
项目摘要
PROJECT SUMMARY
Fractalkine protein (FKN, CX3CL1) suppresses microglial activation leading to decreased
neurodegeneration in a number of neurological disorders, including Alzheimer's disease (AD). In AD, a large
reduction in FKN has been observed in postmortem cortical tissue. We have studied FKN and its role in
neurodegeneration extensively, and we have demonstrated a beneficial effect of FKN in multiple
neurodegenerative disease models. Our work demonstrates that overexpression of a soluble form of FKN
(sFKN) decreases tau pathology in Tg4510 mice. More importantly, we observed that sFKN significantly reduces
brain atrophy and neuron loss in these mice. In Parkinson's disease (PD) mouse models, overexpression of
sFKN, but not a cleavage-resistant, insoluble mutant FKN, reduces disease pathology and neuron loss. Positive
activity with soluble versus membrane-bound FKN suggests that a soluble molecule has the potential to activate
the receptor and achieve neuroprotective effects. These observations prompted the hypothesis that the FKN
pathway could be exploited as a therapeutic approach to treat AD.
High-throughput screening produced a series of chemical scaffolds that are novel small molecule agonists
of CX3CR1 suitable for further optimization through this funding opportunity. The lead compound is potent and
highly selective, and has been shown to reduce LPS-mediated activation of microglia. Here, we propose to
develop orally bioavailable potent CX3CR1 agonist compounds suitable for use as chemical probes. This
campaign leverages the unique resources of Sanford Burnham Prebys and USF Health. Chemistry efforts will
refine the current lead compound to improve potency and selectivity, and enhance the compound's drug-like
properties. These efforts are supported by a robust testing funnel consisting of cellular and biochemical assays
of CX3CR1 signaling, as well as appropriate counter-screens. The physicochemical and pharmacological
properties of the compounds will be optimized, followed by pharmacokinetic studies in rodents. We will test for
target engagement and efficacy in the AD animal models, in which we will identify at least one CX3CR1 agonist
with potent efficacy in vivo.
项目概要
Fractalkine 蛋白(FKN、CX3CL1)抑制小胶质细胞活化,导致
许多神经系统疾病中的神经变性,包括阿尔茨海默病(AD)。在公元,一个大
在死后皮质组织中观察到 FKN 减少。我们研究了 FKN 及其在以下方面的作用:
神经退行性疾病广泛存在,我们已经证明 FKN 在多种疾病中具有有益作用
神经退行性疾病模型。我们的工作表明,可溶形式的 FKN 的过度表达
(sFKN) 降低 Tg4510 小鼠的 tau 病理学。更重要的是,我们观察到 sFKN 显着降低了
这些小鼠的脑萎缩和神经元损失。在帕金森病 (PD) 小鼠模型中,过度表达
sFKN,但不是抗裂解、不溶性突变体 FKN,可减少疾病病理和神经元损失。积极的
可溶性 FKN 与膜结合型 FKN 的活性表明可溶性分子具有激活的潜力
受体并达到神经保护作用。这些观察结果提出了这样的假设:FKN
途径可以作为治疗 AD 的治疗方法。
高通量筛选产生了一系列新型小分子激动剂化学支架
CX3CR1 适合通过此融资机会进一步优化。先导化合物是有效的并且
高度选择性,并已被证明可以减少 LPS 介导的小胶质细胞激活。在此,我们建议
开发适合用作化学探针的口服生物可利用的强效 CX3CR1 激动剂化合物。这
该活动利用了 Sanford Burnham Prebys 和 USF Health 的独特资源。化学方面的努力将
精炼当前的先导化合物以提高效力和选择性,并增强化合物的药物样作用
特性。这些努力得到了由细胞和生化检测组成的强大测试漏斗的支持
CX3CR1 信号传导,以及适当的反筛选。理化和药理
将优化化合物的特性,然后在啮齿动物中进行药代动力学研究。我们将测试
AD 动物模型中的目标参与和功效,其中我们将确定至少一种 CX3CR1 激动剂
在体内具有强大的功效。
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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Kevin Ron Nash其他文献
Kevin Ron Nash的其他文献
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{{ truncateString('Kevin Ron Nash', 18)}}的其他基金
Gene Therapy Rescue of Angelman Syndrome with Reelin
Reelin 基因疗法拯救天使综合症
- 批准号:
10317654 - 财政年份:2021
- 资助金额:
$ 67.71万 - 项目类别:
Targeting neuroinflammation in AD with novel CX3CR1 agonists
使用新型 CX3CR1 激动剂靶向 AD 中的神经炎症
- 批准号:
9919509 - 财政年份:2019
- 资助金额:
$ 67.71万 - 项目类别:
Targeting neuroinflammation in AD with novel CX3CR1 agonists
使用新型 CX3CR1 激动剂靶向 AD 中的神经炎症
- 批准号:
10580679 - 财政年份:2019
- 资助金额:
$ 67.71万 - 项目类别:
Targeting neuroinflammation in AD with novel CX3CR1 agonists
使用新型 CX3CR1 激动剂靶向 AD 中的神经炎症
- 批准号:
10358600 - 财政年份:2019
- 资助金额:
$ 67.71万 - 项目类别:
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