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激活
白介素13受体α1/白介素4受体α(IL-13Rα1/IL-4Rα)复合体的表达
中脑多巴胺(DA)能神经元影响其活性。在大脑中,IL-13Rα1/IL-4Rα唯一表达于
在帕金森病(PD)中丢失的黑质致密部(SNC)神经元。我们还展示了
小胶质细胞和神经元在神经炎症过程中产生的白介素13(IL-13)可以调节
增加多巴胺能细胞的活性,增加其对氧化损伤的敏感性。到目前为止,在以下方面存在差距
了解神经炎症如何导致帕金森病患者DA神经元的选择性丢失。已经确立了
在神经炎症过程中,IL-13Rα1信号的激活可以影响多巴胺能神经元的存活。
在本申请中,我们希望解决这一差距。具体地说,我们希望测试IL-13和
神经元性IL-13Rα1通过刺激一种被称为铁性下垂的受调控的细胞死亡途径而引起损伤。我们也希望
为了确定IL-13和IL-13Rα1在多大程度上促进阿尔茨海默病小鼠模型的神经退行性变。
突触核病(α-SYN),帕金森病的一个特征,与神经炎症和氧化损伤有关。
这将帮助我们确定靶向IL-13Rα1信号是否可能是减缓
受α-突触核苷酸病(如帕金森病)影响的人类神经变性。FDA的Ruxolitinib的能力-
批准的抑制IL-13Rα1信号转导的药物和新型铁下垂抑制剂CMS121的药物,以降低IL-13R
13-介导的体内损伤也将进行测试。最后,我们建议在一种新的小鼠模型上进行活体实验。
为了验证在早发性帕金森病患者中发现的一种罕见的IL-13基因变体可以
与此突变同源的小鼠的多巴胺能神经元更快地丧失。如果
这些实验的成功将为IL-13和IL-13Rα1是新的假说提供强有力的支持
预防帕金森病或减缓其进展的目标,至少在帕金森病患者的子集中是这样。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BRUNO CONTI其他文献
BRUNO CONTI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
- 批准号:
8373865 - 财政年份:2012
- 资助金额:
$ 64.61万 - 项目类别:
相似海外基金
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
- 批准号:
24K11201 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
- 批准号:
24K21101 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
- 批准号:
24K11281 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
- 批准号:
EP/Z001145/1 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Fellowship
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
- 批准号:
2338890 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334777 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334775 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334776 - 财政年份:2024
- 资助金额:
$ 64.61万 - 项目类别:
Continuing Grant
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
- 批准号:
2320040 - 财政年份:2023
- 资助金额:
$ 64.61万 - 项目类别:
Standard Grant
Collaborative Research: CDS&E: An experimentally validated, interactive, data-enabled scientific computing platform for cardiac tissue ablation characterization and monitoring
合作研究:CDS
- 批准号:
2245152 - 财政年份:2023
- 资助金额:
$ 64.61万 - 项目类别:
Standard Grant














{{item.name}}会员




