Anti-inflammatory signals and neurodegeneration
抗炎信号和神经退行性变
基本信息
- 批准号:10928425
- 负责人:
- 金额:$ 64.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-21 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAblationAddressAffectAlzheimer&aposs DiseaseAnimalsAnti-Inflammatory AgentsApoptosisBrainCell DeathCell LineCellsChemosensitizationChronicComplexDataDepositionDevelopmentDiagnosisDiseaseDopaminergic CellFDA approvedFatty-acid synthaseGenerationsGenesGeneticGenetic PolymorphismHomologous GeneHumanHydrogen PeroxideIL-13Ralpha1IL13RA1 geneIn Situ HybridizationIn VitroIndividualInflammatoryInterleukin 4 ReceptorInterleukin-13Interleukin-4IronKnockout MiceLaboratoriesLeucineLinkage DisequilibriumLipid PeroxidesLipopolysaccharidesLoxP-flanked alleleMediatingMicrogliaMidbrain structureModelingMusMutationNerve DegenerationNeurodegenerative DisordersNeuroimmuneNeuronsOdds RatioOxidantsOxidative StressParkinson DiseasePathogenicityPathologyPathway interactionsPatientsPatternPeroxidesPharmaceutical PreparationsPhenotypePositioning AttributePredispositionProlinePublishingReactive Oxygen SpeciesReportingRiskRoleSignal PathwaySignal TransductionSingle Nucleotide PolymorphismSubstantia nigra structureSystemTestingToxic effectTransgenic MiceTyrosine 3-MonooxygenaseVariantVirusWorkX Chromosomealpha synucleincytokinecytotoxicdopaminergic neuronearly onsetexperimental studygain of functiongenetic variantglial activationin vivoinduced pluripotent stem cellinhibitorlocus ceruleus structuremalemitochondrial dysfunctionmouse modelmutantneuroinflammationneuron lossneuroprotectionneurotoxicitynoradrenergicnovelnovel therapeutic interventionoriginalityoxidative damagepars compactapatient subsetsphase I trialpreventreceptorsporadic Parkinson&aposs Diseasesynucleinopathytraittranscriptome
项目摘要
Abstract
Neuroimmune signals regulate neuronal function and survival. We have strong evidence indicating that activation
of the heterodimeric interleukin-13 receptor alpha 1/interleukin-4 receptor alpha (IL-13Rα1/IL-4Rα) complex in
midbrain dopaminergic (DA) neurons affects their viability. In the brain, IL-13Rα1/IL-4Rα is uniquely expressed on
the neurons of the substantia nigra pars compacta (SNc) that are lost in Parkinson’s disease (PD). We also showed
that interleukin 13 (IL-13), produced during neuroinflammation by microglia and neurons, can modulate the
activity of dopaminergic cells and increase their susceptibility to oxidative damage. To date, there is a gap in
understanding how neuroinflammation contributes to the selective loss of DA neurons in PD. Having established
that activation of IL-13Rα1 signaling can affect the survival of dopaminergic neurons during neuroinflammation,
in the present application we wish to address this gap. Specifically, we wish to test the hypothesis that IL-13 and
neuronal IL-13Rα1 cause damage by stimulating a regulated cell death pathway called ferroptosis. We also wish
to determine to what extent IL-13 and IL-13Rα1 contribute to neurodegeneration in a mouse model of alpha-
synucleinopathy (α-Syn), a hallmark trait of PD that is associated with neuroinflammation and oxidative damage.
This will help us determine whether targeting IL-13Rα1 signaling might be a viable approach to slow
neurodegeneration in humans affected by α-synucleinopathy such as PD. The ability of ruxolitinib, an FDA-
approved drug that inhibits IL-13Rα1 signaling and that of the novel ferroptosis inhibitor CMS121, to reduce IL-
13-mediated damage in vivo will also be tested. Finally, we propose in vivo experiments un a novel mouse model
to test the hypothesis that a rare genetic variant of IL-13 found in individuals diagnosed with early-onset PD can
contribute to more rapid loss of dopaminergic neurons in a mouse with the homologue of this mutation. If
successful, these experiments will provide strong support for the hypothesis that IL-13 and IL-13Rα1 are novel
targets for preventing PD or slowing its progression, at least in a sub-set of PD patients.
摘要
神经免疫信号调节神经元的功能和存活。我们有强有力的证据表明
异二聚体白细胞介素-13受体α 1/白细胞介素-4受体α(IL-13 R α1/IL-4 R α)复合物在
中脑多巴胺能(DA)神经元影响其活力。在脑中,IL-13 R α1/IL-4 R α在以下部位独特表达:
帕金森病(PD)中丢失的黑质神经元(SNc)。我们还展示
小胶质细胞和神经元在神经炎症过程中产生的白细胞介素13(IL-13)可以调节
多巴胺能细胞的活性,并增加其对氧化损伤的敏感性。到目前为止,
了解神经炎症如何导致PD中DA神经元的选择性丧失。建立了
IL-13 R α1信号的激活可以影响神经炎症过程中多巴胺能神经元的存活,
在本申请中,我们希望解决这个差距。具体地说,我们希望检验IL-13和
神经元IL-13 R α1通过刺激被称为铁凋亡的调节性细胞死亡途径而引起损伤。我们还要
为了确定IL-13和IL-13 R α1在多大程度上促进了α-SMA小鼠模型中的神经变性,
突触核蛋白病(α-Syn)是PD的标志性特征,与神经炎症和氧化损伤相关。
这将帮助我们确定靶向IL-13 R α1信号转导是否是一种可行的方法,
受α-突触核蛋白病如PD影响的人类神经变性。鲁索利替尼的能力,一个FDA-
批准的药物,抑制IL-13 R α1信号传导和新的铁凋亡抑制剂CMS 121,以减少IL-13 R α1信号传导。
13-还将测试体内介导的损伤。最后,我们提出了一种新的小鼠模型的体内实验,
为了检验在诊断为早发性PD的个体中发现的IL-13的罕见遗传变异体可以
导致具有该突变同源物的小鼠中多巴胺能神经元的更快损失。如果
这些实验的成功将为IL-13和IL-13 R α1是新的假说提供强有力的支持
预防PD或减缓其进展的靶点,至少在PD患者的子集中。
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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BRUNO CONTI其他文献
BRUNO CONTI的其他文献
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{{ truncateString('BRUNO CONTI', 18)}}的其他基金
Calorie Restriction, Body Temperature and Alzheimers Disease
热量限制、体温和阿尔茨海默病
- 批准号:
10727319 - 财政年份:2023
- 资助金额:
$ 64.61万 - 项目类别:
Do allergens contribute to neurodegeneration?
过敏原会导致神经退行性变吗?
- 批准号:
10542643 - 财政年份:2022
- 资助金额:
$ 64.61万 - 项目类别:
Do allergens contribute to neurodegeneration?
过敏原会导致神经退行性变吗?
- 批准号:
10190052 - 财政年份:2021
- 资助金额:
$ 64.61万 - 项目类别:
Role of the IL-13 system in dopaminergic cell death
IL-13系统在多巴胺能细胞死亡中的作用
- 批准号:
8612661 - 财政年份:2013
- 资助金额:
$ 64.61万 - 项目类别:
Role of the IL-13 system in dopaminergic cell death
IL-13系统在多巴胺能细胞死亡中的作用
- 批准号:
9066821 - 财政年份:2013
- 资助金额:
$ 64.61万 - 项目类别:
Role of the IL-13 system in dopaminergic cell death
IL-13系统在多巴胺能细胞死亡中的作用
- 批准号:
9313963 - 财政年份:2013
- 资助金额:
$ 64.61万 - 项目类别:
Role of the IL-13 system in dopaminergic cell death
IL-13系统在多巴胺能细胞死亡中的作用
- 批准号:
8846153 - 财政年份:2013
- 资助金额:
$ 64.61万 - 项目类别:
Role of the IL-13 system in dopaminergic cell death
IL-13系统在多巴胺能细胞死亡中的作用
- 批准号:
8724574 - 财政年份:2013
- 资助金额:
$ 64.61万 - 项目类别:
Brain interleukin-18 control of food intake and energy expenditure
脑白细胞介素 18 控制食物摄入和能量消耗
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8373865 - 财政年份:2012
- 资助金额:
$ 64.61万 - 项目类别:
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