Role of NF-kB in sympathetic hyperreflexia after spinal cord injury
NF-kB在脊髓损伤后交感神经反射亢进中的作用
基本信息
- 批准号:10391321
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmericanAnatomyAnti-Inflammatory AgentsAttenuatedAutoimmune DiseasesAutomobile DrivingAutonomic DysreflexiaAxonBacterial PneumoniaBiochemicalBiological AssayBladderBlood PressureBradycardiaCardiovascular DiseasesCardiovascular systemCellsChestChronicComplexDevelopmentDiseaseDoseExhibitsFDA approvedFecal ImpactionFlow CytometryFrequenciesGlutamatesGoalsHeart RateHyperreflexiaHypertensionImmuneImmune System DiseasesImmunologic Deficiency SyndromesImmunosuppressionImpairmentIndividualInfectionInflammatoryInhibition of NF-KB activationInjuryInterneuronsInterruptionLifeLightMediatingMediator of activation proteinMicrogliaModelingMorbidity - disease rateMyocardial InfarctionNF-kappa BNeuroimmune systemNeuronal PlasticityNeuronsOrganOutputPatientsPeripheralPharmacologyPhenotypePopulationPredispositionProductionPropertyProteinsQuality of lifeQuantitative Reverse Transcriptase PCRReflex actionRegulationRheumatoid ArthritisRiskRodentRoleSecondary toSeveritiesShapesSignal TransductionSiteSpinalSpinal Cord transection injurySpinal cord injurySpleenStrokeSulfasalazineSympathetic Nervous SystemSynapsesSynaptic plasticityTNF geneTelemetryTestingTherapeuticThoracic spinal cord structureTimeTraumaUlcerative Colitisautocrinecytokinedecubitus ulcerglutamatergic signalingimmune functionimprovedinhibitormortalityneural circuitneuronal excitabilitynew therapeutic targetpreventprophylacticresponsesensory inputsensory stimulustranscription factor
项目摘要
PROJECT SUMMARY / ABSTRACT
Cardiovascular disease and immune dysfunction are the two leading causes of morbidity and mortality
in individuals with high-level spinal cord injuries (SCI). This is primarily due to the development of sympathetic
hyperreflexia, which is immediately apparent as an episode of autonomic dysreflexia (AD). AD is a condition
occurring in up to 90% of patients with SCI above thoracic segment 6 that is characterized by life-threatening
hypertension and reflexive bradycardia in response to below-level noxious sensory input. The frequency and
severity of AD episodes progressively increase over time and contribute to increased risk for life-threatening
infections, myocardial infarction, and stroke. The progressive exacerbation of sympathetic hyperreflexia is
thought to be due to maladaptive plasticity within the spinal sympathetic reflex (SSR) circuit which contributes to
heightened sensitivity and exaggerated sympathetic output to critical effector organs, such as vasculature and
the spleen. This neurogenic sympathetic hyperreflexia thereby impairs peripheral immune function and
contributes to systemic immunosuppression that further propagates infection susceptibility. Limiting SSR circuit
plasticity and the development of sympathetic hyperreflexia could therefore have enormous therapeutic
implications in mitigating injury-induced immunosuppression and greatly improve quality of life in individuals with
SCI. Interestingly, the neuroimmune system is implicated as a major underling factor that contributes to the
development of SSR circuit plasticity. Specifically, continued activation of resident microglia local and remote to
the injury site is associated with the production of various proinflammatory cytokines, including soluble tumor
necrosis factor-alpha (sTNFα), that are known to modulate neural circuits. Despite long-term inhibition of sTNFα
after SCI, microglia continue to exhibit a reactive phenotype and there is persistent activation of NF-kB, a
transcription factor complex that is activated by multiple cytokines, well below the SCI. This suggests that reactive
microglia continue to produce a variety of cytokine factors in addition to sTNFα, which continue to activate NF-
kB and thereby establish a pro-inflammatory autocrine loop. Furthermore, NF-kB has been implicated as a key
mediator in chronic inflammatory disorders, such as rheumatoid arthritis, and directly contributes to synaptic and
cellular plasticity. This proposal will focus on the hypothesis that activation of NF-kB after SCI contributes to
driving SSR circuit plasticity that results in the development of sympathetic hyperreflexia and associated AD, as
well as peripheral immune dysfunction. Moreover, we hypothesize that microglial NF-kB signaling alters neuronal
excitability within the SSR circuit. The primary goals of this proposal are to: 1) investigate the role of NF-kB
signaling in the development of sympathetic hyperreflexia (indicated by AD) and resultant dysimmunity (Aim 1);
2) elucidate how SCI-induced NF-kB activity in microglia shapes their phenotype and how that influences
plasticity of neurons within the SSR circuit (Aim 2).
项目摘要/摘要
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 }}
Micaela Lucy O'Reilly其他文献
Micaela Lucy O'Reilly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('Micaela Lucy O'Reilly', 18)}}的其他基金
Role of NF-kB in sympathetic hyperreflexia after spinal cord injury
NF-kB在脊髓损伤后交感神经反射亢进中的作用
- 批准号:
10608108 - 财政年份:2021
- 资助金额:
$ 4.68万 - 项目类别:
相似海外基金
Collaborative Research: REU Site: Earth and Planetary Science and Astrophysics REU at the American Museum of Natural History in Collaboration with the City University of New York
合作研究:REU 地点:地球与行星科学和天体物理学 REU 与纽约市立大学合作,位于美国自然历史博物馆
- 批准号:
2348998 - 财政年份:2025
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Collaborative Research: REU Site: Earth and Planetary Science and Astrophysics REU at the American Museum of Natural History in Collaboration with the City University of New York
合作研究:REU 地点:地球与行星科学和天体物理学 REU 与纽约市立大学合作,位于美国自然历史博物馆
- 批准号:
2348999 - 财政年份:2025
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Collaborative Research: Ionospheric Density Response to American Solar Eclipses Using Coordinated Radio Observations with Modeling Support
合作研究:利用协调射电观测和建模支持对美国日食的电离层密度响应
- 批准号:
2412294 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Conference: Doctoral Consortium at Student Research Workshop at the Annual Conference of the North American Chapter of the Association for Computational Linguistics (NAACL)
会议:计算语言学协会 (NAACL) 北美分会年会学生研究研讨会上的博士联盟
- 批准号:
2415059 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Conference: Polymeric Materials: Science and Engineering Division Centennial Celebration at the Spring 2024 American Chemical Society Meeting
会议:高分子材料:美国化学会 2024 年春季会议科学与工程部百年庆典
- 批准号:
2415569 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Collaborative Research: RUI: Continental-Scale Study of Jura-Cretaceous Basins and Melanges along the Backbone of the North American Cordillera-A Test of Mesozoic Subduction Models
合作研究:RUI:北美科迪勒拉山脊沿线汝拉-白垩纪盆地和混杂岩的大陆尺度研究——中生代俯冲模型的检验
- 批准号:
2346565 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
REU Site: Research Experiences for American Leadership of Industry with Zero Emissions by 2050 (REALIZE-2050)
REU 网站:2050 年美国零排放工业领先地位的研究经验 (REALIZE-2050)
- 批准号:
2349580 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Collaborative Research: RUI: Continental-Scale Study of Jura-Cretaceous Basins and Melanges along the Backbone of the North American Cordillera-A Test of Mesozoic Subduction Models
合作研究:RUI:北美科迪勒拉山脊沿线汝拉-白垩纪盆地和混杂岩的大陆尺度研究——中生代俯冲模型的检验
- 批准号:
2346564 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Conference: Latin American School of Algebraic Geometry
会议:拉丁美洲代数几何学院
- 批准号:
2401164 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant
Conference: North American High Order Methods Con (NAHOMCon)
会议:北美高阶方法大会 (NAHOMCon)
- 批准号:
2333724 - 财政年份:2024
- 资助金额:
$ 4.68万 - 项目类别:
Standard Grant