Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease
Claudin-3、肠道菌群失调和炎症性肠病
基本信息
- 批准号:9888859
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:16S ribosomal RNA sequencing3-DimensionalAcuteAddressAffectApplications GrantsAreaArmy PersonnelAutoimmune DiseasesCell Adhesion MoleculesCell Differentiation processCell PolarityCell-Cell AdhesionCellsChronicChronic DiseaseCitrobacter rodentiumClinical ManagementColitisCollaborationsColonColon CarcinomaCrohn&aposs diseaseDNADataDefectDigestive System DisordersDiseaseDisease ManagementDisease stratificationDisease susceptibilityDysplasiaEconomic BurdenEpithelialEpithelial CellsEpitheliumEtiologyExhibitsGnotobioticGrowthGuidelinesHomeostasisHospitalsIL6 geneIL6ST geneImmuneImmune signalingImpairmentIn VitroIncidenceInfiltrationInflammationInflammatoryInflammatory Bowel DiseasesInterleukin-6Intestinal permeabilityKnowledgeLamina PropriaLeaky GutLife StyleLinkMalignant - descriptorMediatingModelingMolecularMucositisMucous MembraneMusNeoplasmsOrganoidsOutcomePathologyPatientsPilot ProjectsPlayPopulationPredispositionProbioticsProcessProteinsQuality of lifeRegulationReportingResearchRoleSamplingSeriesSeveritiesSeverity of illnessSignal PathwaySignal TransductionSpecificityStressSystemTestingTherapeuticTight JunctionsTissuesUlcerative ColitisVeteransWild Type Mouseburden of illnesscancer cellcancer riskclaudin 3clinically significantcolitis associated cancercolon cancer riskdesensitizationdysbiosisepigenetic regulationepithelium regenerationfecal microbiotagastrointestinal epitheliumgut microbiotahealinghigh riskimprovedin vivo Modelinflammatory milieuinjury and repairintestinal injurymicrobialmouse modelnew therapeutic targetnovel therapeuticsoutcome forecastprognostic significancerepairedtherapeutic target
项目摘要
Inflammatory bowel disease (IBD), consisting primarily of the ulcerative colitis (UC) and Crohn’s disease (CD),
is a group of debilitating auto-immune disorders, which significantly affect one’s life-style and carry a high risk
of colon cancer. While significant advances have been made in the clinical management of these diseases, the
overall incidence rate and disease severity in active duty army personnel and veterans is constantly increasing
possibly due to the high level of stress involved. Moreover, IBD significantly increases the risk of colon cancer,
and therefore physical and economical burden of these diseases upon our veteran population is significantly
high. However, the etiology of IBD remains unclear. Taken together, there is an urgent and unmet need for
improved understanding of the molecular mechanisms that promote IBD susceptibility and/or disease severity,
as it can help identify novel therapeutic targets. In this regard, disruption of epithelial polarity and
compartmentalization, assisted by the tight junction (TJ) deregulation, plays key role in inducing and promoting
mucosal inflammation. Notably, an association between the leaky gut and IBD has long been suggested.
However, despite this knowledge, progress in this area for therapeutic gains has been limited due primarily to
the generic perspective that proteins constituting the TJ are static and redundant in their function. This proposal
disagrees with this generic view and proposes key role of claudin-3, a TJ-integral protein, in dynamic regulation
of the gut epithelial and inflammatory homeostasis. Our working hypothesis is that the loss of claudin-3, which
characterizes IBD patients, deregulates mucosal barrier integrity to induce gut dysbiosis and pro-inflammatory
environment. Accompanying deregulations of gp130/IL6/Stat3 and Hippo/Yap signaling cascades, due to the
polarity defects ensued by deregulated Par-3 expression, render chronicity to the initial inflammatory insult by
deregulating mucosal injury/repair leading ultimately to neoplastic growth.
This proposal is built upon a strong scientific premise as a series of studies, including ours, have now
identified claudin-3 (hereon Cldn3) as a key TJ-protein in maintaining gut epithelial barrier maturity and integrity.
In this regard, we found Cldn3 to be the highest expressed cell-cell adhesion protein localized primarily amongst
differentiated colonocyte at the crypt top in normal colon. Furthermore, Cldn3KO mice, used to model decreased
Cldn3 levels in IBD patients, exhibited hyper-permeable gut and immune cell infiltration into the lamina propria.
In addition, gut dysbiosis along with specific and robust increase in gp130/IL6/Stat3 expression characterized
Cldn3KO mice. Cldn3 loss also compromised colonic epithelial cell (CEC) differentiation and polarity, and
promoted Hippo/Yap-signaling. Importantly, Stat-3 and Yap-signaling pathways promote hyper-proliferation,
chronic inflammation and malignant growth when deregulated. Accordingly, DSS colitis-challenged Cldn3KO
mice exhibited severe colitis and dysplasia (versus WT-mice). Taken together, our data support the role of Cldn3
as a rheostat in regulating the colonic epithelial and immune signaling and thereby leading to the hypothesis that
Cldn3 loss is promiscuous in promoting colitis. To test our hypothesis, we propose following studies: Aim-1. To
determine the expression dynamics and context for the loss of Cldn3 expression in promoting IBD; Aim-2. To
determine the role and potential collaboration between IL6/Stat3 and Hippo/Yap signaling in promoting colitis
under conditions of the loss of Cldn3 expression; and Aim-3. To determine the causal integration between Cldn3
loss and gut dysbiosis in promoting IBD. Overall, this proposal presents a unique platform for dissecting circuity
between mucosal barrier deregulation and polarity in regulating colitis and associated cancer for therapeutic
gains. Outcome will be significant in improving survival and quality of life of our Veterans.
炎症性肠病(IBD),主要包括溃疡性结肠炎(UC)和克罗恩病(CD),
是一组衰弱的自身免疫性疾病,显著影响一个人的生活方式,具有很高的风险
结肠癌。虽然在这些疾病的临床管理方面取得了重大进展,但
现役军人和退伍军人的总体发病率和疾病严重程度不断上升
可能是因为压力很大。此外,IBD显著增加了患结肠癌的风险,
因此,这些疾病给我们的退伍军人带来了巨大的身体和经济负担
很高。然而,IBD的病因仍不清楚。综上所述,存在着一种迫切而未得到满足的需求
提高对促进IBD易感性和/或疾病严重性的分子机制的理解,
因为它可以帮助确定新的治疗靶点。在这方面,上皮极性的破坏和
在紧密连接(TJ)放松管制的辅助下,区分化在诱导和促进方面发挥着关键作用
粘膜发炎。值得注意的是,长期以来,人们一直认为肠道渗漏与IBD之间存在联系。
然而,尽管有这些知识,但这一领域在治疗方面的进展一直有限,主要是因为
一种普遍的观点,认为构成TJ的蛋白质在功能上是静态的和多余的。这项建议
不同意这种普遍的观点,并提出了TJ整合蛋白claudin-3在动态调节中的关键作用
肠道上皮和炎症的动态平衡。我们的工作假设是claudin-3的丢失,它
IBD患者的特征,解除对粘膜屏障完整性的管制,以诱导肠道生态失调和促炎
环境。伴随着gp130/IL6/STAT3和Hippo/YAP信号级联的放松管制,由于
PAR-3表达失控导致的极性缺陷,使慢性化成为最初的炎症性损害
解除对粘膜损伤/修复的调控,最终导致肿瘤生长。
这一建议是建立在强大的科学前提之上的,包括我们在内的一系列研究现在已经
Claudin-3(以下简称Cldn3)是维持肠上皮屏障成熟度和完整性的关键蛋白。
在这方面,我们发现cldn3是表达最高的细胞-细胞黏附蛋白,主要定位于
正常结肠隐窝顶端有分化的结肠癌细胞。此外,用于造模的Cldn3KO小鼠的数量减少
在IBD患者中,Cldn3水平表现为肠道高通透性和免疫细胞向固有层渗透。
此外,肠道生物失调伴随着gp130/IL6/STAT3表达的特异性和强劲的增加是其特征
Cldn3KO小鼠。Cldn3缺失还损害了结肠上皮细胞(CEC)的分化和极性,以及
推广河马/YAP信号。重要的是,Stat-3和YAP信号通路促进了过度增殖,
当解除管制时,慢性炎症和恶性生长。因此,DSS结肠炎挑战Cldn3KO
小鼠表现出严重的结肠炎和发育不良(与WT小鼠相比)。总之,我们的数据支持Cldn3的作用
作为变阻器调节结肠上皮和免疫信号,从而导致假设
Cldn3缺失在促进结肠炎方面是杂乱无章的。为了验证我们的假设,我们提出了以下研究:Aim-1。至
确定在促进IBD过程中Cldn3表达缺失的表达动力学和背景;AIM-2。至
确定IL6/STAT3和Hippo/YAP信号在促进结肠炎中的作用和潜在的协作
在Cldn3表达缺失的条件下;Aim-3。确定Cldn3之间的因果整合
在促进IBD方面的损失和肠道代谢失调。总体而言,这项提议提供了一个剖析电路的独特平台
黏膜屏障去调节和极性在调节结肠炎和相关癌症治疗中的作用
收获。结果将对改善我们退伍军人的生存和生活质量具有重要意义。
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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Amar B Singh其他文献
Amar B Singh的其他文献
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{{ truncateString('Amar B Singh', 18)}}的其他基金
Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease
Claudin-3、肠道菌群失调和炎症性肠病
- 批准号:
10455414 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease
Claudin-3、肠道菌群失调和炎症性肠病
- 批准号:
10620269 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
- 批准号:
8187549 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
- 批准号:
8469855 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
- 批准号:
8309950 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
- 批准号:
8970129 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
- 批准号:
8666745 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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