Targeting the sphingosine-1-phosphate system in a mouse model of Gulf War Veterans' Illness
针对海湾战争退伍军人疾病小鼠模型中的 1-磷酸鞘氨醇系统
基本信息
- 批准号:10293531
- 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:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholinesteraseAcetylcholinesterase InhibitorsAffectAffectiveAnimal ModelAnimalsAnti-Inflammatory AgentsAnxietyAstrocytesAttentional deficitAxonBehaviorBehavior assessmentBehavioralBiological AssayBloodBrainBrain-Derived Neurotrophic FactorBreathingBromidesC-reactive proteinCerebral cortexChemical WarfareChronicClinical TrialsCognitionCognitiveComplement 3cComplete Blood CountComplexCongenital neurologic anomaliesDataDiseaseDisease MarkerDoseDrug DesignDrug TargetingEncephalitisEnzyme-Linked Immunosorbent AssayEtiologyExhibitsExposure toFatigueFemaleFunctional disorderGenderGlial Fibrillary Acidic ProteinGulf War veteranHeadacheHippocampus (Brain)Human ResourcesImmunoassayImpaired cognitionInfiltrationInflammationInflammatoryInsect RepellentsInsectaInsecticidesIntestinesLinkLocomotionLongitudinal StudiesLymphocyteLymphocyte CountMeasuresMemoryMental DepressionMethodologyMicrogliaMilitary PersonnelModelingMolecularMonitorMotor ActivityMultiple SclerosisMusNervous system structureNeuraxisNeurologic SymptomsNeurological ModelsNeuronsOligodendrogliaPainPatientsPeripheralPermethrinPharmaceutical PreparationsPharmacologyPlatelet Count measurementPlatelet aggregationPotassium ChannelProcessProductionProteomicsRelapsing-Remitting Multiple SclerosisReportingResearchResearch DesignResearch MethodologyResearch PersonnelRoleSarinSerumSignal TransductionSkin AbnormalitiesSodium ChannelSphingosine-1-Phosphate ReceptorStomachStressSymptomsSystemTechniquesTestingTherapeuticThinkingThromboxanesTimeVeteransWarWestern BlottingWomananalogbaseblood-brain barrier crossingcell determinationcholinergicclinical practiceconditioned fearcytokineefficacy evaluationfear memoryfield studyforced swim testgray matterimaging studyimmune functionimmune system functionimprovedindexinginnovationmalemenmonocytemouse modelmultiple sclerosis treatmentnerve agentnervous system disorderneurochemistryneuroinflammationneurotrophic factorneutrophilnovelpersistent symptompreclinical trialpreventpyridostigmineremyelinationresponsesexual dimorphismsphingosine 1-phosphatesuccesstargeted agenttreatment effect
项目摘要
The pathophysiology of Gulf War Veterans’ Illness (GWVI) remains poorly understood, and treatments are lack-
ing. Neurological symptoms including cognitive impairment, attention deficits, depression, and anxiety are a top
complaint among GWVI patients. GWVI may be the result of exposure to drugs designed to protect military
personnel from a chemical attack and from insects. These include: 1) pyridostigmine bromide (PB), 2) permethrin
(PER), and 3) diethyltoluamide (DEET). Although these drugs are considered safe at the doses administered to
GW personnel, it has been hypothesized that their combination together with the stress of war may have con-
tributed synergistically to generate the GWVI. We have used an animal model of GWVI based on this hypothesis
by exposing mice to relevant doses of PB, PER, DEET and stress and found anxiety, brain neuroinflammation,
cholinergic, GABAergic and neurotrophic factor abnormalities as latent post-exposure markers of this disease.
Some changes were sexually dimorphic indicating that the pathophysiology of GWVI and responses to potential
treatments may be different in men and women. Our data provide evidence for a neuroinflammatory process in
brains of GWVI-model animals, which is characterized by astrocyte and microglia activation in the hippocampus
that correlates with the increased level of anxiety and memory abnormalities seen in the model and can be
related to reports indicating aberrant immune function and chronic inflammation in GWVI patients. Therefore, we
propose to use our mouse model of GWVI to test the hypothesis that GWVI may be ameliorated by targeting
neuroinflammation using fingolimod, a drug that targets the sphingosine-1-phosphate receptor and is used for
the treatment of relapsing remitting multiple sclerosis (RRMS). In RRMS it prevents the infiltration of lymphocytes
into the CNS, promotes remyelination, and exerts neuroprotective effects on astrocytes. We propose to deter-
mine the efficacy of fingolimod on ameliorating the delayed and persistent GWVI-related behavioral, cellular and
molecular CNS abnormalities in male and female mice. Based on our preliminary data, the use of a high and low
dose of fingolimod will allow us to differentiate the drug’s peripheral versus central action. We will assess the
treatment effect on: a) behavior using specific animal paradigms for assessing anxiety, locomotion, memory, and
depression; b) neuroinflammation measured with multiplexed proteomic immunoassays of cytokine panels and
by immunohistochemical determinations of cells expressing Iba1 and GFAP; c) BDNF levels and signaling by
ELISA and immunohistochemical assays; d) indices of cholinergic and GABAergic function by Western blot; e)
peripheral measures of inflammation by complete blood count and serum cytokine panel assays. This study
incorporates rational pharmacology with state-of-the-art neuropathological and neurochemical techniques to-
gether with cognitive and affective behavioral assessment to advance therapeutic strategies for GWVI.
海湾战争退伍军人病(GWVI)的病理生理学仍然知之甚少,治疗缺乏
项目成果
期刊论文数量(0)
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ALPASLAN DEDEOGLU其他文献
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{{ truncateString('ALPASLAN DEDEOGLU', 18)}}的其他基金
Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis
1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点
- 批准号:
10011983 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis
1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点
- 批准号:
10664897 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis
1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点
- 批准号:
10476986 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Protective roles of taurine in Alzheimer's disease brain
牛磺酸对阿尔茨海默病大脑的保护作用
- 批准号:
10055586 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Targeting the sphingosine-1-phosphate system in a mouse model of Gulf War Veterans' Illness
针对海湾战争退伍军人疾病小鼠模型中的 1-磷酸鞘氨醇系统
- 批准号:
9891211 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Sphingosine-1-phosphate induced modulation of inflammation in aging and Alzheimer's disease
1-磷酸鞘氨醇诱导衰老和阿尔茨海默病炎症的调节
- 批准号:
9403429 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
- 批准号:
8815008 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
- 批准号:
8974377 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
- 批准号:
8660378 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
- 批准号:
9339554 - 财政年份:2014
- 资助金额:
-- - 项目类别:
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