Mechanisms Underlying Regulation of Susceptibility to CNS Autoimmunity by Commensal Lactobacillus Species
共生乳杆菌对中枢神经系统自身免疫易感性的调节机制
基本信息
- 批准号:10312423
- 负责人:
- 金额:$ 2.96万
- 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:2021-09-01 至 2022-08-14
- 项目状态:已结题
- 来源:
- 关键词:Adoptive TransferAffectAllelesAnimal ModelAppointmentAstrocytesAutoimmunityAxonBlood - brain barrier anatomyBlood CirculationBrainCD8-Positive T-LymphocytesCNS autoimmune diseaseCNS autoimmunityCellsCentral Nervous System DiseasesChronicClinical TrialsCommunicationComplexCore FacilityCoupledDataDemyelinationsDevelopmentDietDiseaseDisease ResistanceDisease susceptibilityDistalEnvironmentEnvironmental Risk FactorEtiologyExhibitsExperimental Autoimmune EncephalomyelitisFlow CytometryFutureGenesGeneticGenomicsGranulocyte-Macrophage Colony-Stimulating FactorHealth SciencesHumanImmuneImmune systemImmunologyIncidenceIndolesInflammatoryIntakeInterventionKnowledgeLactobacillusLactobacillus reuteriLesionMass Spectrum AnalysisMedicineMentorsMentorshipMetabolicMicrobiologyMicrogliaMolecular GeneticsMultiple SclerosisMusMyelinNeuraxisNeurodegenerative DisordersNeurogliaNeurologicNeurologic DysfunctionsPathogenesisPathologyPeripheralPersonsPhasePhysiologyPopulationPredispositionProductionRegulationResource SharingRiskRisk FactorsRoleScienceSeverity of illnessShapesSiteSmokingStressSymptomsT cell responseT-LymphocyteTechniquesTestingTherapeuticTrainingTryptophanTryptophan Metabolism PathwayUniversitiesVermontVitamin Dblood-brain barrier permeabilizationcollegecommensal microbesdietarydisabilityeducational atmosphereeffector T cellgenome sequencinggut bacteriagut microbiomegut microbiotaimmunoregulationin vitro Assayin vivomembermetabolomicsmicrobialmicrobiomemicrobiotamicrobiota transplantationmicroorganismmouse modelmultidisciplinarymultiple sclerosis patientmultiple sclerosis treatmentneuroimmunologyneuroinflammationneuropathologynovelpersonalized medicineresident commensalsresponseskillswhole genomeyoung adult
项目摘要
Project Summary:
Multiple sclerosis (MS) is a chronic autoimmune central nervous system (CNS) disease and the leading cause
of non-traumatic neurological disability in young adults. The cause of MS is complex and cannot be ascribed to
any single gene with over 70% risk attributed to environmental factors. Recent studies identified an imbalance
in the human gut microbiome within MS patients as one such environmental risk, including depletion of the
Lactobacillus genus. Animal models support a causal role for the gut microbiome in MS, though the mechanism
remains unclear. Utilizing a mouse model of MS, we have identified disease resistant and susceptible
microbiomes, with stark differences in Lactobacillus species abundance and notable differences in their
circulating metabolic by-products known to modulate the immune system. Further, we have identified a single
commensal species, Lactobacillus reuteri (L. reuteri), which is sufficient to accentuate MS-like symptoms in the
mouse with whole genome sequencing indicating the necessary enzymatic machinery to account for the
observed differences in circulating metabolites. The focus of this proposal is to 1) determine the cellular
mechanisms underlying the effects of L. reuteri on EAE including both impact on infiltrating peripheral immune
cells and CNS resident glial cells and 2) determine the impact of L. reuteri-derived tryptophan metabolites on
neuroinflammation.
In direct support of the proposed studies, the training plan will develop the knowledge, expertise, scientific
communication skills and technical abilities in 1) mouse models of multiple sclerosis focused on host interactions
with the gut microbiome including directed microbiome manipulation, 2) immunology, with a focus on
neuroimmunology, flow cytometry, and functional assays in vitro and in vivo, 3) microbiology, with a focus on
commensal gut bacteria, their culture, isolation, genomic and metabolic characterization, and manipulation, 4)
neuropathology, with a focus on techniques to investigate CNS pathology to characterize inflammatory
demyelinating lesions in CNS autoimmune disease and blood brain barrier integrity analysis and 5)
metabolomics with a focus on bacterial metabolites and their effects on host physiology.
The training environment at the University of Vermont (UVM) is multidisciplinary with a collegial atmosphere that
stresses active mentorship and as such is uniquely appropriate to support this proposal which bridges
autoimmunity, CNS neuropathology and commensal microbiota. This is evidenced by co-mentors with
appointments in the departments of Biomedical and Health Sciences (BHSC), Microbiology and Molecular
Genetics (MMG), and Neurological Sciences which are connected to a hub of core facilities and the Larner
College of Medicine offering ample opportunity to share resources and promote in-person communication.
项目概要:
多发性硬化症 (MS) 是一种慢性自身免疫性中枢神经系统 (CNS) 疾病,也是导致该病的主要原因
年轻人的非创伤性神经功能障碍。 MS 的病因很复杂,不能归咎于
超过 70% 的风险归因于环境因素的任何单一基因。最近的研究发现了不平衡
多发性硬化症患者的人类肠道微生物组中存在这样的环境风险之一,包括
乳酸菌属。动物模型支持肠道微生物组在多发性硬化症中的因果作用,尽管其机制
仍不清楚。利用多发性硬化症小鼠模型,我们已经确定了抗病性和易感性
微生物组,乳酸菌物种丰度存在明显差异,且其数量也存在显着差异
已知可调节免疫系统的循环代谢副产物。此外,我们还确定了一个
共生菌,罗伊氏乳杆菌 (L. reuteri),足以加重 MS 样症状
小鼠全基因组测序表明必要的酶机制来解释
观察到循环代谢物的差异。该提案的重点是 1) 确定蜂窝
罗伊氏乳杆菌对 EAE 影响的机制,包括对浸润性外周免疫的影响
细胞和中枢神经系统驻留神经胶质细胞,2) 确定路伊氏乳杆菌来源的色氨酸代谢物对
神经炎症。
为了直接支持拟议的研究,培训计划将培养知识、专业知识、科学
1)多发性硬化症小鼠模型的沟通技巧和技术能力,重点关注宿主相互作用
肠道微生物组,包括定向微生物组操作,2) 免疫学,重点是
神经免疫学、流式细胞术以及体外和体内功能测定,3) 微生物学,重点是
共生肠道细菌、其培养、分离、基因组和代谢特征以及操作,4)
神经病理学,重点是研究中枢神经系统病理学以表征炎症的技术
中枢神经系统自身免疫性疾病脱髓鞘病变及血脑屏障完整性分析5)
代谢组学,重点研究细菌代谢物及其对宿主生理学的影响。
佛蒙特大学 (UVM) 的培训环境是多学科的,具有学院氛围,
强调积极的指导,因此非常适合支持这项弥合桥梁的提案
自身免疫、中枢神经系统神经病理学和共生微生物群。共同导师证明了这一点
生物医学和健康科学(BHSC)、微生物学和分子学系的任命
遗传学(MMG)和神经科学与核心设施和拉纳中心相连
医学院提供充足的机会共享资源和促进面对面的交流。
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 }}
Theresa Lynn Montgomery其他文献
Theresa Lynn Montgomery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('Theresa Lynn Montgomery', 18)}}的其他基金
Mechanisms Underlying Regulation of Susceptibility to CNS Autoimmunity by Commensal Lactobacillus Species
共生乳杆菌对中枢神经系统自身免疫易感性的调节机制
- 批准号:
10516032 - 财政年份:2021
- 资助金额:
$ 2.96万 - 项目类别:
相似国自然基金
KIR3DL1等位基因启动子序列变异影响其差异表达的分子机制研究
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
NUP205双等位基因突变影响纤毛发生而致内脏转位合并先天性心脏病的机理研究
- 批准号:
- 批准年份:2021
- 资助金额:54 万元
- 项目类别:面上项目
全基因组范围内揭示杂交肉兔等位基因特异性表达模式对杂种优势遗传基础的影响
- 批准号:32102530
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
等位基因不平衡表达对采后香蕉果实后熟与品质形成的影响
- 批准号:31972471
- 批准年份:2019
- 资助金额:57 万元
- 项目类别:面上项目
高温影响水稻不同Wx等位基因表达及直链淀粉含量的分子机制研究
- 批准号:31500972
- 批准年份:2015
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
相似海外基金
The role of SH2B3 in regulating CD8 T cells in Type 1 Diabetes
SH2B3 在 1 型糖尿病中调节 CD8 T 细胞的作用
- 批准号:
10574346 - 财政年份:2023
- 资助金额:
$ 2.96万 - 项目类别:
Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
- 批准号:
10682121 - 财政年份:2023
- 资助金额:
$ 2.96万 - 项目类别:
Alpha-Synuclein-Specific T cells in Parkinson's Disease Pathogenesis
帕金森病发病机制中的α-突触核蛋白特异性 T 细胞
- 批准号:
10752172 - 财政年份:2023
- 资助金额:
$ 2.96万 - 项目类别:
Mechanisms Underlying Regulation of Susceptibility to CNS Autoimmunity by Commensal Lactobacillus Species
共生乳杆菌对中枢神经系统自身免疫易感性的调节机制
- 批准号:
10516032 - 财政年份:2021
- 资助金额:
$ 2.96万 - 项目类别:
Gamma delta T cell based melanoma therapies
基于 Gamma Delta T 细胞的黑色素瘤疗法
- 批准号:
10365762 - 财政年份:2021
- 资助金额:
$ 2.96万 - 项目类别: