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
• 负责人: Bobak Parang
• 金额: $ 2.67万
• 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/8724489
• 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（由申请人提供）：炎症性肠病（IBD）影响美国约140万人，并伴有多种严重并发症，如瘘管、狭窄和结直肠癌风险增加。IBD的所谓解释是可能由微生物群触发的免疫系统的持续不适当激活。事实上，肠上皮细胞持续暴露于巨大的抗原负荷并受到其挑战。值得注意的是，尽管持续损伤，肠上皮仍保持稳态。伤口愈合程序中的缺陷正在成为IBD发病机制中的关键因素。然而，伤口愈合程序仍然很复杂，而且遗传因素在起作用还没有被牢固地确立。 上皮细胞向间质细胞转化（Epithelial-to-mesenchymal transition，EMT）是上皮细胞获得更多间质细胞表型的关键过程，如更强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）是在发育中的心脏的cDNA筛选中发现的紧密连接相关蛋白。最近，已经证明BVES的丧失促进角膜上皮细胞系和恶性细胞系中的EMT。此外，敲低BVES表达破坏细胞与细胞粘附，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EMT程序最近被牵连在IBD的发病机制。鉴于这些观察结果，我们假设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在上皮修复程序中起着关键作用。我们建议测试这一假设，并扩大我们的理解如何BVES通知细胞内信号通路的两个集中的具体目标。首先，我们将使用两种互补的结肠炎动物模型在BVES-/-小鼠中诱导肠损伤：葡聚糖硫酸钠（DSS）和啮齿类柠檬酸杆菌感染。这些将使我们能够确定BVES缺陷小鼠是否更容易患结肠炎。第二，我们已经委托酵母双杂交筛选，并确定PR 61-alpha，一种与细胞生长和增殖相关的磷酸酶，作为BVES的结合伴侣。我们将测试这种相互作用的功能意义，通过映射的结合域，并确定如何破坏相互作用影响BVES依赖的表型和细胞内信号。我们提出的研究将确定BVES在IBD病理学和损伤修复程序中的作用。重要的是，阐明BVES的作用可能会创造新的治疗途径。