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
• 负责人: Bobak Parang
• 金额: $ 2.71万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8921977
• 关键词: Abdominal Pain; Acute; Affect; Anchorage-Independent Growth; Animal Model; Antigens; Apoptosis; Area; Binding; Biological Process; Blood Vessels; Body Weight Changes; Cell Adhesion; Cell Line; Cell Proliferation; Cells; Chemicals; Chronic; Citrobacter rodentium; Clinical; Clinical Data; Co-Immunoprecipitations; Colitis; Colon; Colorectal; Colorectal Cancer; Complementary DNA; Complex; Data; Defect; Development; Epithelial; Epithelial Cells; Epithelium; Feces; Fistula; Genetic; Guanine; Guanine Nucleotide Exchange Factors; Healed; Heart; Homeostasis; Immune system; Impaired wound healing; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestines; Link; Maps; Mesenchymal; Modeling; Molecular; Molecular Analysis; Monitor; Mucous Membrane; Mus; Nature; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Physicians; Play; Process; Protein phosphatase; Proteins; RNA; Research Personnel; Resistance; Rho-associated kinase; Risk; Role; Sampling; Scientist; Severities; Severity of illness; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; Surface; Testing; Tight Junctions; Tissues; Trauma; United States; Wound Healing; Yeasts; cancer cell; carcinogenesis; cell growth; cell motility; corneal epithelium; epithelial to mesenchymal transition; experience; healing; human disease; in vivo; injury and repair; intestinal epithelium; knock-down; microorganism; migration; pathogen; prevent; programs; repaired; research study; response to injury; yeast two hybrid system

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.

描述(申请人提供)：炎症性肠病(IBD)在美国影响着大约140万人，并带有许多严重的并发症，如瘘管、狭窄和结直肠癌的高风险。所谓的IBD的解释是一种持续的、不适当的免疫系统激活，可能是由微生物群引发的。事实上，肠道上皮不断地暴露在巨大的抗原负荷下并受到挑战。值得注意的是，尽管不断受到损伤，肠上皮仍保持动态平衡。伤口愈合程序中的缺陷在IBD的发病机制中发挥着关键作用。然而，伤口愈合程序仍然很复杂，发挥作用的遗传因素尚未得到确定。上皮向间充质转化(EMT)是上皮细胞获得更多间充质表型的关键过程，如更大的运动性和锚定独立性，在损伤修复中起关键作用。血管心外膜物质(BVES)是在心脏发育过程中发现的一种紧密连接相关蛋白。最近的研究表明，BVES的缺失促进了角膜上皮细胞和恶性细胞系的EMT。此外，下调BVES的表达会破坏细胞间的黏附，加速迁移、侵袭和锚定非依赖性生长，并增加增殖。有趣的是，异常的EMT程序最近被认为与IBD的发病机制有关。鉴于这些观察结果，我们推测BVES可能参与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在上皮修复程序中起着关键作用。我们建议检验这一假设，并通过两个特定的目标来扩大我们对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：葡聚糖硫酸钠(DSS)和轮状柠檬酸杆菌感染来诱导BVES-/-小鼠的肠道损伤。这将使我们能够确定BVES缺陷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，并确定与细胞生长和增殖相关的磷酸酶PR61-α是BVES的结合伙伴。我们将通过绘制结合结构域并确定破坏相互作用如何影响BVES依赖的表型和细胞内信号，来测试这种相互作用的功能意义。我们建议的研究将确定BVES在IBD病理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。