Investigation of Ferroptosis as a Therapeutic Target for ALS
铁死亡作为 ALS 治疗靶点的研究
基本信息
- 批准号:10588525
- 负责人:
- 金额:--
- 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:2023-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAffectAmyotrophic Lateral SclerosisApoptosisAstrocytesCell DeathCellsCessation of lifeDegenerative DisorderDiseaseEffectivenessInterventionInvestigationIronLifeLongevityModalityMotor Neuron DiseaseMotor NeuronsMusNeurogliaNeuronsOnset of illnessParalysedPathogenesisProductionReportingResearchRiskRoleSpinalStressSymptomsSyndromeSystemTestingTherapeuticTissuesUterusVertebral columnVeteranscell typecohortefficacious treatmentefficacy evaluationefficacy testingglutathione peroxidaseimprovedin vivoinducible gene expressioninsightmilitary servicemotor neuron degenerationmouse modelneuron lossnovelnovel therapeutic interventionoverexpressionprotective efficacysmall moleculesporadic amyotrophic lateral sclerosistherapeutic target
项目摘要
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron degenerative disease that leads to
paralysis and eventual death. ALS is a particular concern for veterans, as military service is associated with
increased risk of ALS. The root cause of ALS is the death of motor neurons; however, the modalities of motor
neuron death in ALS remain unclear. Ferroptosis is an oxidative, iron-dependent cell death mechanism. Results
from our prior research have shown that motor neurons are vulnerable to ferroptosis. Importantly, we showed
recently that increased defense against ferroptosis resulted in significantly increased lifespan and ameliorated
motor neuron degeneration in SOD1G93A mice, a widely used ALS mouse model, indicating that ferroptosis is
a targetable vulnerability of motor neurons. However, at present, key questions about the roles of ferroptosis in
motor neuron death of ALS remain unanswered. For example, it is unclear whether inhibition of ferroptosis at
symptomatic stage can retard progression of motor neuron disease, and the contributions of ferroptotic stress of
different cell types on pathogenesis of motor neuron disease remain unknown. To answer those questions, we
have generated a novel mouse model with inducible expression of Gpx4, the master defender of ferroptosis,
which allows us to inhibit ferroptosis genetically in both temporal and cell-type specific manners. In our
preliminary study, we have also identified a small molecule compound with the ability to retard ferroptosis of
motor neurons in vivo. To determine if ferroptosis-inhibiting compounds can retard motor neuron disease, we
will test the efficacy of this compound in SOD1G93A mice. The overall hypothesis tested in this project is:
inhibition of ferroptosis after disease onset will be effective in retarding progression of motor neuron disease and
ferroptosis inhibition retards motor neuron disease in a cell-type specific manner. The results from this project
will provide novel insights into the mechanisms of motor neuron degeneration of ALS, and importantly, could
lead to new therapeutic strategies for ALS.
肌萎缩侧索硬化症(ALS)是一种毁灭性的运动神经元退行性疾病,导致
项目成果
期刊论文数量(0)
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{{ truncateString('QITAO RAN', 18)}}的其他基金
Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease
膜脂质过氧化在阿尔茨海默病发病机制中的作用
- 批准号:
10615076 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease
膜脂质过氧化在阿尔茨海默病发病机制中的作用
- 批准号:
10396534 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Gpx4 and ferroptosis inhibition in retarding ALS
Gpx4 和铁死亡抑制可延缓 ALS
- 批准号:
10158408 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Gpx4 and ferroptosis inhibition in retarding ALS
Gpx4 和铁死亡抑制可延缓 ALS
- 批准号:
9898290 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Mitochondrial ROS in environmental toxin-induced AD pathogenesis
环境毒素诱导的 AD 发病机制中的线粒体 ROS
- 批准号:
8239669 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Mitochondrial ROS in environmental toxin-induced AD pathogenesis
环境毒素诱导的 AD 发病机制中的线粒体 ROS
- 批准号:
8445156 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Mitochondrial ROS in environmental toxin-induced AD pathogenesis
环境毒素诱导的 AD 发病机制中的线粒体 ROS
- 批准号:
8698294 - 财政年份:2012
- 资助金额:
-- - 项目类别:
The preventive and therapeutic potential of reducing mitochondrial H2O2 for AD
减少线粒体 H2O2 对 AD 的预防和治疗潜力
- 批准号:
8195924 - 财政年份:2009
- 资助金额:
-- - 项目类别:
The preventive and therapeutic potential of reducing mitochondrial H2O2 for AD
减少线粒体 H2O2 对 AD 的预防和治疗潜力
- 批准号:
7780446 - 财政年份:2009
- 资助金额:
-- - 项目类别:
The preventive and therapeutic potential of reducing mitochondrial H2O2 for AD
减少线粒体 H2O2 对 AD 的预防和治疗潜力
- 批准号:
7683614 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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