Microbiota, Tertiary Lymphoid Structures and Chronic Inflammation in the Human Gut
微生物群、三级淋巴结构和人类肠道慢性炎症
基本信息
- 批准号:10385741
- 负责人:
- 金额:$ 19.75万
- 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:2021-04-06 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAnimal ModelAntibody ResponseAntigen-Presenting CellsAntigensAreaAtherosclerosisAutoimmuneAutoimmune DiseasesAutoimmunityB-LymphocytesBindingBiologyCell FractionCell SeparationCell modelCell surfaceCellsChronicChronic DiseaseChronic GastritisClinicalCoinCollaborationsColorectal CancerCrohn&aposs diseaseData SetDefectDendritic CellsDevelopmentDiseaseDrug or chemical Tissue DistributionExcisionFlow CytometryFunctional disorderFutureGastroenterologyGastrointestinal tract structureGene ExpressionGenerationsGeneticGraft RejectionHeterogeneityHumanImmuneImmune responseImmunoglobulin AImmunoglobulin GImmunologyInfectious colitisInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseIntestinesLifeLinkLymphoidMalignant NeoplasmsMetagenomicsMethodologyMicrobeMicroscopyMolecularMononuclearMucous MembraneMusOperative Surgical ProceduresOrganOutcomePathogenesisPathogenicityPathologyPathway AnalysisPatientsPhagocytesPhenotypePlasma CellsPopulationPositioning AttributePrognostic FactorPublicationsPublishingReactionReportingResourcesSalmonellaSalmonella infectionsScienceShotgunsSiteSpecificitySystemT-LymphocyteTestingTissuesUlcerative ColitisViralbacteriomecancer typecheckpoint therapycommensal microbesgastrointestinalgraft vs host diseasegut microbiotahost-microbe interactionshuman modellymph nodesmacrophagemedical schoolsmicrobialmicrobiotamucosal sitemultidisciplinarymultiple omicsnovel therapeutic interventionnovel therapeuticspathobiontresponsesalmonella colitissecondary lymphoid organtertiary lymphoid organtranscriptome sequencingvirome
项目摘要
PROJECT SUMMARY
Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates with the cellular composition
resembling secondary lymphoid organs. Although the exact function of TLS remains elusive, the accumulated
evidence suggests that TLS significantly contribute to the pathogenesis of chronic disorders including
autoimmune and inflammatory diseases, graft versus host disease, transplant rejection, and various types of
cancer. Therefore, better understanding of the composition of TLS and specificity of the immune response that
they initiate in the context of a specific disease may help decode the disease pathogenesis and provide novel
therapeutic strategies.
Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is
thought to result from the dysregulated immune response to commensal microbes driven by a convergence of
genetic, environmental and microbial factors. Studies in humans and animal models indicate that IBD
pathogenesis is associated with dysregulated mononuclear phagocyte (MP) system and abnormal T and B cell
responses. We recently identified the mechanisms that drive TLS development in mice with Salmonella colitis.
In this new study we will take advantage of our expertise, established collaboration and clinical resources
available at UMass Medical School (UMMS) to understand the mechanisms that drive TLS development and
function in human IBD. Our overarching hypothesis is that TLS in IBD are dysregulated towards a preferential
generation of local proinflammatory IgG response instead of IgA and are induced by specific inflammatory MP
subsets in response to pathobionts that colonize the mucosa. To test the hypothesis, we are going to analyze
intestinal surgical resections from patients with IBD by applying a combination of multi-OMICs approaches. Our
actively collaborating multi-disciplinary team that consists of experts in MP biology, computational biomedicine,
bacterial microbiome, virome, gastroenterology and clinical GI pathology is uniquely positioned to address the
following specific aims:
Aim 1. Establish cellular composition and predict intercellular interactions in TLS in human IBD;
Aim 2. Identify pathobionts that drive TLS formation via MP activation in human IBD.
As the outcome of this project, we will establish a model of cell-cell and cell-microbe interactions and
identify key regulatory molecules required for development of intestinal TLS in human IBD. Short term, these
results will provide a basis for our future R01 proposal that will test computational predictions of host-microbial
interactions and link them to disease pathogenesis with the underlying rationale to identify novel therapeutic
avenues aimed at TLS in IBD. In the long term, information and methodology gained from this study will be
applied to other inflammatory and autoimmune conditions as well as cancers in which TLS formation is evident.
项目概要
三级淋巴结构 (TLS) 是具有细胞成分的异位紊乱淋巴聚集体
类似于次级淋巴器官。尽管 TLS 的确切功能仍然难以捉摸,但累积的
有证据表明 TLS 显着促进慢性疾病的发病机制,包括
自身免疫性疾病和炎症性疾病、移植物抗宿主病、移植排斥和各种类型的
癌症。因此,更好地了解 TLS 的组成和免疫反应的特异性
它们在特定疾病的背景下启动可能有助于解码疾病的发病机制并提供新的
治疗策略。
炎症性肠病 (IBD),包括克罗恩病 (CD) 和溃疡性结肠炎 (UC),
被认为是由于对共生微生物的免疫反应失调造成的,这种免疫反应是由多种因素共同驱动的
遗传、环境和微生物因素。人类和动物模型研究表明 IBD
发病机制与单核吞噬细胞 (MP) 系统失调以及 T 和 B 细胞异常有关
回应。我们最近发现了沙门氏菌结肠炎小鼠中驱动 TLS 发育的机制。
在这项新研究中,我们将利用我们的专业知识、已建立的合作和临床资源
可在麻省大学医学院 (UMMS) 了解驱动 TLS 开发的机制和
在人类 IBD 中的功能。我们的首要假设是 IBD 中的 TLS 失调,倾向于优先选择
产生局部促炎 IgG 反应而不是 IgA,并由特定的炎症 MP 诱导
对定植于粘膜的病原体作出反应的亚群。为了检验假设,我们将分析
通过结合多组学方法对 IBD 患者进行肠道手术切除。我们的
积极合作的多学科团队,由 MP 生物学、计算生物医学、
细菌微生物组、病毒组、胃肠病学和临床胃肠道病理学具有独特的地位来解决
以下具体目标:
目标 1. 建立人类 IBD 中 TLS 的细胞组成并预测细胞间相互作用;
目标 2. 识别在人类 IBD 中通过 MP 激活驱动 TLS 形成的病原体。
作为该项目的成果,我们将建立细胞-细胞和细胞-微生物相互作用的模型,
确定人类 IBD 肠道 TLS 发育所需的关键调节分子。短期来看,这些
结果将为我们未来的 R01 提案提供基础,该提案将测试宿主微生物的计算预测
相互作用并将它们与疾病发病机制联系起来,并找出新的治疗方法的基本原理
针对 IBD 中 TLS 的途径。从长远来看,从这项研究中获得的信息和方法将
适用于其他炎症和自身免疫性疾病以及 TLS 形成明显的癌症。
项目成果
期刊论文数量(2)
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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Milena Bogunovic其他文献
Milena Bogunovic的其他文献
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{{ truncateString('Milena Bogunovic', 18)}}的其他基金
Microbiota, Tertiary Lymphoid Structures and Chronic Inflammation in the Human Gut
微生物群、三级淋巴结构和人类肠道慢性炎症
- 批准号:
10154604 - 财政年份:2021
- 资助金额:
$ 19.75万 - 项目类别:
Integration of Enteric Immune and Nervous Systems in the Mucosal Recall Immune Response
肠道免疫和神经系统在粘膜回忆免疫反应中的整合
- 批准号:
9335274 - 财政年份:2016
- 资助金额:
$ 19.75万 - 项目类别:
Mucosal Macrophages and Tertiary Lymphoid Structures in IBD
IBD 中的粘膜巨噬细胞和三级淋巴结构
- 批准号:
10605344 - 财政年份:2016
- 资助金额:
$ 19.75万 - 项目类别:
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