Intestinal IL-17RA signaling and mucosal host defense
Intestinal IL-17RA signaling and mucosal host defense
批准号:
10605304
负责人:
Pawan Kumar
金额:
$41.3万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-07-01 至 2025-04-30
关键词:
Abnormal CellAdverse eventAnti-Inflammatory AgentsAntibodiesAreaCell Differentiation processCell LineageCell physiologyCellsClinical TrialsCollaborationsComplexCoupledCrohn&aposs diseaseDataDiseaseEndocrineEnteralEnterocytesEnvironmentEpithelial CellsEpitheliumGastrointestinal tract structureGenerationsGoalsGoblet CellsGrowth FactorHomologous GeneHost DefenseHumanIL17 geneImmune responseInfectionInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInjuryIntestinesInvestigationKnockout MiceKnowledgeLGR5 geneLarge IntestineLiteratureMaintenanceMediatingModelingMolecularMolecular Mechanisms of ActionMucous MembraneMuramidaseMusPaneth CellsPathogenicityPathway interactionsPatientsPersonsPlayPredispositionQualifyingReceptor SignalingRegulationResearchRoleSecretory CellSignal TransductionSmall IntestinesSodium Dextran SulfateTamoxifenTestingTherapeuticTissuesUlcerative ColitisUnited StatesUniversitiesVirulence Factorsalpha-Defensinsantimicrobialcell typecommensal bacteriaconditional knockoutcytokinedefense responsedesigndextran sulfate sodium induced colitisdysbiosisexperiencegastrointestinal epitheliumgut inflammationgut microbiotain vivoinsightintestinal epitheliumintestinal injuryirradiationknockout animalmicrobiotamouse modelneutralizing antibodynovelpleiotropismpreservationprogenitorreceptorregenerativeresponseresponse to injurystem cell functionstem cell nichestem cellssynergismtooltranscription factorvillin
中文摘要
炎症性肠病(IBD)包括溃疡性结肠炎(UC)和克罗恩病(CD),是一种
影响美国数百万人的毁灭性疾病。主导的潜在机制
人们对IBD知之甚少。Paneth细胞及其抗菌产物(a-防御素、溶菌酶等)播放
在小肠宿主防御中的关键作用及其失调构成了CD的致病因素。光盘
患者存在潘氏细胞异常,α-防御素表达减少,IL-17A水平升高
发炎的组织。IL-17A/IL-17F轴是肠道炎症和保护性的已知驱动因素
在小鼠模型和人类IBD模型中的反应,但对IL-2的特定细胞生态位知之甚少。
肠道17A/F受体信号转导及IL-17A介导宿主防御的分子机制我们
我们首次表明,消除肠道IL-17A宿主防御反应会导致共生
小肠中的生物失调和免疫反应失调。尽管有无数的胃肠道疾病
对于IL-17A刺激的肠道反应,文献未能阐明是否对
损伤或感染是直接刺激功能不同的吸收或分泌成熟的结果。
无论是上皮细胞类型还是干细胞衍生的结果。因此,目前尚不清楚IL-17A
直接或间接地调节肠道中的Paneth和其他细胞类型的效应器功能。我们发现IL-17A/F
受体(IL-17RA/IL-17RC)表达于功能不同的吸收细胞(肠细胞)、分泌细胞
(Paneth)、Lgr5+肠道干细胞(ISCs)和肠道转运扩增(TA)祖细胞。
然而,关于IL-17A是否直接或间接调节Paneth细胞,ISCs,几乎一无所知
和祖细胞的功能。我们现在有令人信服的证据表明IL-17A直接调节
在肠道的Paneth细胞、ISCs和Atoh1+祖细胞中具有独特和特定的功能。Atoh1是
肠道分泌细胞,包括潘氏细胞的谱系承诺所必需的。为了调查血统-
特定的功能,我们建立并验证了完整的肠道上皮(Villin-cre)、Paneth细胞(Defa6-cre)和
Atoh1特异性(Atoh1-cre)新型IL-17RA(Il17rafl/fl)条件性基因敲除小鼠。目标1中的拟议研究
将试图了解IL-17RA信号在调节ISC和Paneth细胞功能中的作用
动态平衡状态。在目标2中,使用多种肠道炎症模型和我们的谱系特异性IL-2
17RA条件性基因敲除小鼠,我们将确定IL-17A如何在特定的
小肠和大肠的细胞类型。这些研究将对IBD研究产生直接影响
了解IL-17RA信号转导小肠和大肠主要细胞类型的新作用。完成
这些研究将提供对IL-2作用的复杂分子机制的必要了解。
17A在调节肠道炎症中的作用。
英文摘要
Inflammatory bowel disease (IBD), which comprises Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a
devastating disease that impacts millions of people in the United States. The underlying mechanisms leading
to IBD are poorly understood. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a
critical role in small intestinal host defense and their dysregulation constitutes a pathogenic factor for CD. CD
patients have Paneth cell abnormalities, reduced expression of a-defensins and elevated levels of IL-17A in
the inflamed tissue. The IL-17A/IL-17F axis is a known driver of intestinal inflammatory and protective
responses in mouse models and human IBD, but little is known regarding the specific cellular niches of IL-
17A/F receptor signaling and the molecular mechanisms of IL-17A-mediated host defense in the intestines. We
were the first to show that the abrogation of intestinal IL-17A host defense responses leads to commensal
dysbiosis and dysregulated immune responses in the small intestine. Despite the myriad of gastrointestinal
tract responses to IL-17A stimulation, the literature has failed to elucidate whether the defense responses to
injury or infection are a result of direct stimulation to functionally distinct absorptive or secretory mature
epithelial cell types or if they are stem cell-derived consequences. Therefore, it is not known whether IL-17A
directly or indirectly modulates Paneth and other cell types effector function in the gut. We found that IL-17A/F
receptor (IL-17RA/IL-17RC) is expressed on functionally distinct absorptive cells (enterocytes), secretory cells
(Paneth), Lgr5+ intestinal stem cells (ISCs) and transit-amplifying (TA) progenitor cells of the intestine.
However, almost nothing is known regarding whether IL-17A directly or indirectly modulates Paneth cells, ISCs
and progenitor cells function. We now have compelling evidence suggesting that IL-17A directly regulates
unique and specific functions in Paneth cells, ISCs and ATOH1+ progenitor cells of intestine. ATOH1 is
required for lineage commitment of intestinal secretory cells, including Paneth cells. To investigate lineage-
specific function, we generated and validated entire gut epithelium (Villin-cre), Paneth cell (Defa6-cre) and
Atoh1-specific (Atoh1-cre) novel IL-17RA (Il17rafl/fl) conditional knockout mice. The proposed studies in Aim 1
will seek to understand the role of IL-17RA signaling in regulating ISC and Paneth cell function under
homeostatic conditions. In Aim 2, using multiple models of intestinal inflammation and our lineage-specific IL-
17RA conditional knockout mice, we will determine how IL-17A regulates unique and novel functions in specific
cell types in the small and large intestine, respectively. These studies will have a direct impact in IBD research
to understand the novel role of IL-17RA signaling major cell types of the small and large intestine. Completion
of these studies will provide a needed understanding of the complex molecular mechanisms of actions of IL-
17A in regulating intestinal inflammation.
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依托单位:
Intestinal IL-17RA signaling and mucosal host defense
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批准号:10395928
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项目类别:
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资助金额:$41.3万
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财政年份:2019
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负责人:Pawan Kumar
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依托单位:
海外基金