Role of the spinal cord - gut - immune axis after spinal cord injury
脊髓损伤后脊髓-肠道-免疫轴的作用
基本信息
- 批准号:9380128
- 负责人:
- 金额:$ 54.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-15 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAnemiaAnimalsAntibioticsAutonomic nervous systemBacteriaBladderBloodBone MarrowBrainBrain StemButyratesClinicalColonCommunitiesComorbidityDataDatabasesDecentralizationDeteriorationDevelopmentDietDiseaseDistalEcologyEpigenetic ProcessEpithelialFemaleFoundationsFunctional disorderFutureGastrointestinal tract structureGene ExpressionGeneticGenetic TranscriptionGenomeGerm-FreeGoalsHealthHomeostasisHumanImmuneImmune systemImmunologicsImmunosuppressionImpairmentInfectionInflammationInflammatoryInfusion proceduresInjuryInterventionIntestinesLearningLesionMaintenanceMeasuresMediatingMedicalMetabolic syndromeMicrobeMolecular TargetMusMyelopoiesisNervous system structureNeurologicNeuronsNutraceuticalOralOrganOrganismOutcomeParalysedPathologicPathologyPermeabilityPhenotypePhysiologyPopulationProbioticsQuality of lifeRecoveryRecovery of FunctionReflex actionRegulatory T-LymphocyteResearch Project GrantsRodentRodent ModelRoleSerotoninSeveritiesSpinalSpinal CordSpinal InjuriesSpinal cord injuryStimulusSuspensionsSympathetic Nervous SystemSystemTechnologyTestingTherapeuticTight JunctionsTimeTracerTranslational ResearchTryptophanbiomarker panelbody systemcell motilitycellular targetingclinically relevantcommensal microbesexperimental studyfecal transplantationfeedingfunctional disabilitygut microbiomegut microbiotaimmune functionimmunoregulationimprintimprovedinnovationmacrophagemalemetagenomic sequencingmicrobial communitymicrobiomemicrobiotamouse modelneuroprotectionnovelprobiotic therapyrepairedrestorationsex
项目摘要
Abstract
Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS), impairing the
ability of the ANS to coordinate organ function throughout the body. Emerging data
indicate that systemic pathology resulting from ANS dysfunction contributes to
intraspinal pathology and neurological impairment. For example, the post-injury onset of
neurogenic bowel and immune suppression can cause gut dysbiosis – a pathological
state where beneficial symbiotic bacteria (probionts) in the GI tract become
outnumbered by aggressive bacteria (pathobionts). Recent data from our lab show that
SCI triggers gut dysbiosis, which impairs functional recovery and exacerbates lesion
pathology. Since different types of gut bacteria exert unique effects on the host and
these effects can vary by sex, it is important to understand how gut ecology changes as
a function of time, spinal injury level and injury severity in both males and females.
Accordingly, experiments in Aim 1 will use state-of-the-art PhyloChip technology to
profile post-SCI changes in gut microbial communities in male and female mice as a
function of injury severity, time post-injury and injury level. The primary goal is to identify
post-injury changes in gut microbe populations that could be manipulated for therapeutic
gain. Gut microbe manipulation is clinically feasible and can profoundly affect
mammalian physiology. Indeed, we found that functional recovery is improved and lesion
pathology reduced in mice treated post-SCI with a medical-grade probiotic (VSL#3).
Aim 2 will explore the mechanisms underlying VSL#3-mediated neuroprotection. SCI
can affect the gut microbiome but the altered microbiota can in turn affect the immune
system and spinal cord. Aim 3 will examine how SCI-induced gut dysbiosis influences
macrophage phenotype and function. Emerging data indicate that gut microbes can
cause transcriptional and epigenetic changes in macrophage precursors in bone marrow.
Such changes can render mature macrophages more or less responsive to subsequent
inflammatory stimuli, including those found in the injured spinal cord. Using germ-free
mice (devoid of any commensal microbe) and fecal transplantation to selectively
recolonize mice with control or SCI microbiota, we will test whether gut dysbiosis
adversely affects macrophage function. Rather than “treat the spinal cord”, this proposal
seeks new ways to treat SCI as a systemic disorder caused by breakdown of the spinal
cord-gut-immune axis.
摘要
脊髓损伤(SCI)破坏自主神经系统(ANS),损害神经系统的功能。
ANS协调全身器官功能的能力。新出现的数据
表明由ANS功能障碍引起全身病理学有助于
脊柱内病理学和神经损伤。例如,损伤后的
神经源性肠道和免疫抑制可导致肠道生态失调-一种病理性
说明胃肠道中的有益共生细菌(益生菌)
数量超过了侵略性细菌(致病菌)。我们实验室的最新数据显示,
SCI触发肠道生态失调,损害功能恢复并加重病变
病理由于不同类型的肠道细菌对宿主产生独特的影响,
这些影响可能因性别而异,重要的是要了解肠道生态如何变化,
男性和女性的时间、脊柱损伤水平和损伤严重程度的函数。
因此,目标1中的实验将使用最先进的PhyloChip技术,
在雄性和雌性小鼠的肠道微生物群落中,
损伤程度、伤后时间和损伤程度的函数关系。主要目标是识别
损伤后肠道微生物群的变化,可用于治疗
增益肠道微生物操作在临床上是可行的,
哺乳动物生理学事实上,我们发现功能恢复得到改善,
在SCI后用医用级益生菌(VSL#3)治疗的小鼠中病理学减少。
目的2将探索VSLI #3介导的神经保护作用的潜在机制。SCI
可以影响肠道微生物群,但改变的微生物群反过来又会影响免疫系统。
系统和脊髓。目标3将研究SCI诱导的肠道生态失调如何影响
巨噬细胞表型和功能。新的数据表明,肠道微生物可以
引起骨髓中巨噬细胞前体的转录和表观遗传变化。
这种变化可以使成熟的巨噬细胞或多或少地对随后的免疫应答反应。
炎症刺激,包括在受伤的脊髓中发现的那些。使用无菌
小鼠(没有任何肠道微生物)和粪便移植,以选择性地
用对照或SCI微生物群对小鼠进行接种,我们将测试肠道生态失调是否
对巨噬细胞功能有不利影响。而不是“治疗脊髓”,这一建议
寻求新的方法来治疗脊髓损伤,这是一种由脊髓损伤引起的系统性疾病,
索肠免疫轴
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)
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PHILLIP G POPOVICH其他文献
PHILLIP G POPOVICH的其他文献
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{{ truncateString('PHILLIP G POPOVICH', 18)}}的其他基金
Eighteenth International Symposium on Neural Regeneration (ISNR)
第十八届国际神经再生研讨会(ISNR)
- 批准号:
9913669 - 财政年份:2019
- 资助金额:
$ 54.52万 - 项目类别:
Overcoming Neurogenic “Meta-Inflammation” to Promote Recovery After Spinal Cord Injury
克服神经源性“元炎症”以促进脊髓损伤后的恢复
- 批准号:
10634510 - 财政年份:2019
- 资助金额:
$ 54.52万 - 项目类别:
Overcoming Neurogenic “Meta-Inflammation” to Promote Recovery After Spinal Cord Injury
克服神经源性“元炎症”以促进脊髓损伤后的恢复
- 批准号:
10400875 - 财政年份:2019
- 资助金额:
$ 54.52万 - 项目类别:
Overcoming neurogenic “meta-inflammation” to promote recovery after spinal cord injury
克服神经源性“元炎症”以促进脊髓损伤后的恢复
- 批准号:
9924658 - 财政年份:2019
- 资助金额:
$ 54.52万 - 项目类别:
Overcoming Neurogenic “Meta-Inflammation” to Promote Recovery After Spinal Cord Injury
克服神经源性“元炎症”以促进脊髓损伤后的恢复
- 批准号:
10160976 - 财政年份:2019
- 资助金额:
$ 54.52万 - 项目类别:
Preventing autonomic dysreflexia to restore immune function after SCI
预防 SCI 后自主神经反射异常以恢复免疫功能
- 批准号:
8812278 - 财政年份:2014
- 资助金额:
$ 54.52万 - 项目类别:
TREM2 regulation of macrophages in spinal cord injury and CNS endogenous repair
TREM2对脊髓损伤和中枢神经系统内源性修复中巨噬细胞的调节
- 批准号:
8024876 - 财政年份:2011
- 资助金额:
$ 54.52万 - 项目类别:
TREM2 regulation of macrophages in spinal cord injury and CNS endogenous repair
TREM2对脊髓损伤和中枢神经系统内源性修复中巨噬细胞的调节
- 批准号:
8311626 - 财政年份:2011
- 资助金额:
$ 54.52万 - 项目类别:
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