The Role of BVES in Intestinal Repair Programs and Inflammatory Bowel Disease
BVES 在肠道修复计划和炎症性肠病中的作用
基本信息
- 批准号:8453603
- 负责人:
- 金额:$ 2.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-18 至 2016-09-17
- 项目状态:已结题
- 来源:
- 关键词:Abdominal PainAcuteAffectAnchorage-Independent GrowthAnimal ModelAntigensApoptosisAreaBindingBiological ProcessBlood VesselsBody Weight ChangesCell AdhesionCell LineCell ProliferationCellsChemicalsChronicCitrobacter rodentiumClinicalClinical DataCo-ImmunoprecipitationsColitisColonColorectalColorectal CancerComplementary DNAComplexDataDefectDevelopmentEpithelialEpithelial CellsEpitheliumFecesFistulaGeneticGuanineGuanine Nucleotide Exchange FactorsHealedHeartHomeostasisImmune systemImpaired wound healingIn VitroInfectionInflammationInflammatoryInflammatory Bowel DiseasesInjuryIntestinesLinkMapsMesenchymalModelingMolecularMolecular AnalysisMonitorMucous MembraneMusNatureOxidative StressPathogenesisPathologyPathway interactionsPatientsPhenotypePhosphoric Monoester HydrolasesPhysiciansPlayProcessProtein phosphataseProteinsRNAResearch PersonnelResistanceRho-associated kinaseRiskRoleSamplingScientistSeveritiesSeverity of illnessSignal PathwaySignal TransductionSodium Dextran SulfateSurfaceTestingTight JunctionsTissuesTraumaUnited StatesWound HealingYeastscancer cellcarcinogenesiscell growthcell motilitycorneal epitheliumepithelial to mesenchymal transitionexperiencehealinghuman diseasein vivoinjury and repairintestinal epitheliumknock-downmicroorganismmigrationpathogenpreventprogramsrepairedresearch studyresponse to injuryyeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States, and carries numerous and severe complications, such as fistulas, strictures, and heightened risk of colorectal cancer. The purported explanation of IBD is a persistent inappropriate activation of the immune system possibly triggered by the microbiota. Indeed, the intestinal epithelium is continually exposed to and challenged by a tremendous antigen load. Remarkably, the intestinal epithelium maintains homeostasis despite continually sustaining injury. Defects in wound healing programs are emerging as playing a key role in contributing to IBD pathogenesis. Wound healing programs remain complex, however, and the genetic factors in play have yet to be firmly established. Epithelial-to-mesenchymal transition (EMT) is a critical process by which epithelial cells acquire more mesenchymal phenotypes, such as greater motility and anchorage independence, and it is pivotal in injury repair. Blood vessel epicardial substance (BVES) is a tight junction associated protein discovered in a cDNA screen of a developing heart. Recently, it has been demonstrated that loss of BVES promotes EMT in corneal epithelial and malignant cell lines. Furthermore, knocking down BVES expression disrupts cell-to-cell adhesion, accelerates migration, invasion, and anchorage independent growth and increases proliferation. Interestingly, aberrant EMT programs have recently been implicated in the pathogenesis of IBD. Given these observations we postulate that BVES could contribute to the pathogenesis of IBD. In support of this, we found that BVES levels in IBD patients were inversely correlated to disease severity. Taken together, we hypothesize that BVES plays a critical role in epithelial repair programs. We propose to test this hypothesis and expand our understanding of how BVES informs intracellular signaling pathways by two focused specific aims. First, we will induce intestinal injury in BVES-/- mice using two complementary animals models of colitis: dextran sodium sulfate (DSS) and Citrobacter rodentium infection. These will allow us to determine whether BVES deficient mice are more susceptible to colitis. Second, we have commissioned a yeast-two-hybrid screen and identified PR61-alpha, a phosphatase linked to cell growth and proliferation, as a binding partner of BVES. We will test the functional significance of this interaction by mapping the binding domains and by determining how disrupting the interaction affects BVES-dependent phenotypes and intracellular signaling. Our proposed studies will define the role of BVES in IBD pathology and injury repair programs. Importantly, clarifying the role of BVES could potentially create new avenues of therapy.
PUBLIC HEALTH RELEVANCE: Project Narrative Inflammatory bowel disease (IBD) affects approximately 1.4 million individuals in the United States, and despite exciting advances in recent IBD research, we still lack a complete understanding of the disease, impeding breakthroughs in treatment. Our data suggests that BVES, a protein involved in forming cell-to-cell interactions, may contribute to IBD. We propose to investigate thoroughly the contribution of BVES to IBD by using animal models as well as cellular experimentation with the ultimate goal of deciphering how BVES can be targeted therapeutically.
描述(由申请人提供):炎症性肠病 (IBD) 在美国影响着大约 140 万人,并会带来许多严重的并发症,例如瘘管、狭窄和结直肠癌的高风险。 IBD 的据称解释是可能由微生物群触发的免疫系统持续不适当的激活。事实上,肠上皮不断暴露于巨大的抗原负荷并受到挑战。值得注意的是,尽管持续受到损伤,肠上皮仍保持体内平衡。伤口愈合程序的缺陷正在成为 IBD 发病机制的关键因素。然而,伤口愈合程序仍然很复杂,并且起作用的遗传因素尚未确定。 上皮间质转化(EMT)是上皮细胞获得更多间质表型的关键过程,例如更大的运动性和锚定独立性,并且它在损伤修复中至关重要。血管心外膜物质 (BVES) 是在发育心脏的 cDNA 筛选中发现的一种紧密连接相关蛋白。最近,已经证明 BVES 的缺失会促进角膜上皮细胞和恶性细胞系的 EMT。此外,敲低 BVES 表达会破坏细胞间粘附,加速迁移、侵袭和贴壁独立生长并增加增殖。有趣的是,异常的 EMT 计划最近与 IBD 的发病机制有关。鉴于这些观察结果,我们推测 BVES 可能有助于 IBD 的发病机制。为了支持这一点,我们发现 IBD 患者的 BVES 水平与疾病严重程度呈负相关。综上所述,我们假设 BVES 在上皮修复程序中发挥着关键作用。我们建议通过两个重点具体目标来检验这一假设,并扩大我们对 BVES 如何通知细胞内信号通路的理解。首先,我们将使用两种互补的结肠炎动物模型诱导 BVES-/- 小鼠肠道损伤:葡聚糖硫酸钠 (DSS) 和柠檬酸杆菌感染。这些将使我们能够确定 BVES 缺陷的小鼠是否更容易患结肠炎。其次,我们委托进行了酵母双杂交筛选,并鉴定了 PR61-α(一种与细胞生长和增殖相关的磷酸酶)作为 BVES 的结合伴侣。我们将通过绘制结合域图谱并确定破坏相互作用如何影响 BVES 依赖性表型和细胞内信号传导来测试这种相互作用的功能意义。我们提出的研究将定义 BVES 在 IBD 病理学和损伤修复计划中的作用。重要的是,阐明 BVES 的作用可能会创造新的治疗途径。
公共健康相关性:项目叙述炎症性肠病 (IBD) 影响着美国大约 140 万人,尽管最近 IBD 研究取得了令人兴奋的进展,但我们仍然对该疾病缺乏完整的了解,阻碍了治疗的突破。我们的数据表明,BVES(一种参与形成细胞间相互作用的蛋白质)可能会导致 IBD。我们建议通过使用动物模型和细胞实验来彻底研究 BVES 对 IBD 的影响,最终目标是破译 BVES 如何进行靶向治疗。
项目成果
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{{ truncateString('Bobak Parang', 18)}}的其他基金
The Role of BVES in Intestinal Repair Programs and Inflammatory Bowel Disease
BVES 在肠道修复计划和炎症性肠病中的作用
- 批准号:
8572975 - 财政年份:2012
- 资助金额:
$ 2.62万 - 项目类别:
The Role of BVES in Intestinal Repair Programs and Inflammatory Bowel Disease
BVES 在肠道修复计划和炎症性肠病中的作用
- 批准号:
8921977 - 财政年份:2012
- 资助金额:
$ 2.62万 - 项目类别:
The Role of BVES in Intestinal Repair Programs and Inflammatory Bowel Disease
BVES 在肠道修复计划和炎症性肠病中的作用
- 批准号:
8724489 - 财政年份:2012
- 资助金额:
$ 2.62万 - 项目类别:
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