Modulation of astrocyte-mediated neurotoxicity by NR1D1 in ALS models
ALS 模型中 NR1D1 调节星形胶质细胞介导的神经毒性
基本信息
- 批准号:10800001
- 负责人:
- 金额:$ 53.78万
- 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:2023-04-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ALS patientsAdultAgonistAmyotrophic Lateral SclerosisAstrocytesAutopsyBrain StemCause of DeathCell Culture TechniquesCellsCentral Nervous SystemCircadian RhythmsCoculture TechniquesDataDiseaseDisease ProgressionDown-RegulationFibroblastsFunctional disorderGenesGoalsHomeostasisHumanInflammationInflammatoryInflammatory ResponseLinkMammalsMediatingMetabolicMetabolismMitochondriaModelingMolecularMotor CortexMotor Neuron DiseaseMotor NeuronsMovementMusMuscle WeaknessNF-kappa BNerve DegenerationNeurogliaNeuronsNuclear ReceptorsParalysedPathologicPathway interactionsPhenotypePlayProcessProteinsProteomicsRegulationReportingRoleSignal TransductionSkeletal MuscleSpecificitySpinal CordSymptomsTestingTherapeuticTissuesToxic effectTranscription RepressorTransgenic Organismsadeno-associated viral vectorcell typedefined contributionfamilial amyotrophic lateral sclerosisflexibilityfused in sarcomagene therapyglucose metabolismin vivoinduced pluripotent stem cellinsightknock-downlipid metabolismmembermetabolomicsmitochondrial dysfunctionmolecular clockmotor neuron degenerationmouse modelmultiple omicsmutantnerve stem cellneuroinflammationneuron lossneuronal survivalneurotoxicneurotoxicitynew therapeutic targetnovelnovel therapeutic interventionoverexpressionpharmacologicpre-clinicalsmall moleculesuperoxide dismutase 1transcriptomics
项目摘要
Abstract
ALS or Lou Gehrig's disease is the most common adult-onset motor neuron disease, characterized by the
progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Motor neuron death
leads to muscle weakness and paralysis, usually causing death in one to five years after symptoms onset. The
molecular mechanisms responsible for motor neuron degeneration in ALS remain uncertain. However, several
lines of evidence indicate that dysfunction of glial cells significantly contributes to the neurodegenerative process.
Astrocytes, key regulators of central nervous system homeostasis, have been shown to play a major role in the
progression of the disease. Accordingly, in cell culture models, astrocytes isolated from ALS mouse models or
astrocytes differentiated from fibroblast-derived induced pluripotent stem cells (iPSCs) from sporadic and familial
ALS patients, induce motor neuron death. Astrocytes have a key role in the metabolic support of neurons, and
lack of metabolic flexibility and mitochondrial dysfunction are hallmarks of ALS astrocytes. We recently showed
that NR1D1 plays a critical role in the regulation of astrocyte-motor neuron interaction. NR1D1 is a member of
the nuclear receptor superfamily and it is an essential component of the molecular clock in mammals. NR1D1 is
also a known repressor of metabolic and inflammatory genes, and has been shown to regulate mitochondrial
number and function, glucose and lipid metabolism, and inflammation during normal and pathological conditions.
We recently reported that NR1D1 expression decreases in the spinal cord of symptomatic ALS mice. Moreover,
we showed that the knockdown of Nr1d1 expression in primary mouse spinal cord astrocyte cultures, or in iPSC-
derived human astrocytes, activates NF-kB signaling and induces a pro-inflammatory phenotype that is
detrimental for the survival of co-cultured motor neurons. In addition, our preliminary data shows that iPSC-
derived astrocytes from ALS patients display lower levels of NR1D1 expression when compared to astrocytes
derived from healthy controls. In this proposal, we will investigate the role of NR1D1 in the regulation of astrocyte-
motor neuron interaction and the therapeutic potential of targeting NR1D1 in ALS. We will perform an unbiased
multi-omic analysis to outline the mechanism by which NR1D1 downregulation induces a neurotoxic phenotype
in human iPSC-derived astrocytes (Aim 1). In addition, we will use different approaches to evaluate the effect of
modulating NR1D1 expression on the progression of the disease in an ALS mouse model (Aims 2 and 3). The
results obtained will contribute to the current understanding of the mechanisms involved in the toxicity of
astrocytes towards motor neurons in ALS. In addition, this proposal will establish the therapeutic value of
targeting NR1D1 to slow or halt the progression of the disease in an ALS mouse model.
摘要
项目成果
期刊论文数量(0)
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Mariana Atina Pehar其他文献
Mariana Atina Pehar的其他文献
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{{ truncateString('Mariana Atina Pehar', 18)}}的其他基金
A link between lipid-mediated signaling and inflammation during neurodegeneration
神经变性过程中脂质介导的信号传导与炎症之间的联系
- 批准号:
10701487 - 财政年份:2023
- 资助金额:
$ 53.78万 - 项目类别:
NGF and RAGE-p75NTR signaling in models of amyotrophic lateral sclerosis
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10058850 - 财政年份:2017
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