Role of eosinophils in intestinal epithelial dysfunction

嗜酸性粒细胞在肠上皮功能障碍中的作用

• 批准号: 7850224
• 负责人: GLENN T FURUTA
• 金额: $ 0.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850224
• 关键词: Adrenal Cortex Hormones; Affect; Allergic; Apical; Asthma; Atopic Dermatitis; Body Weight decreased; Cells; Clinical; Colon; Cytoplasmic Granules; Data; Deposition; Development; Diagnostic; Diagnostic tests; Diarrhea; Disease; Elements; Eosinophil Granule Proteins; Eosinophil cationic protein; Eosinophil-Derived Neurotoxin; Eosinophilia; Eosinophilic Colitis; Epithelial; Epithelial Cells; Epithelium; Esophagus; Food; Food Hypersensitivity; Functional disorder; Gastroesophageal reflux disease; Gastrointestinal tract structure; Gene Expression; Goals; Hemorrhage; Human; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-5; Intestines; Knockout Mice; Knowledge; Lamina Propria; Little' s Disease; Malabsorption Syndromes; Measures; Mediating; Microarray Analysis; Modeling; Molecular; Mucous Membrane; Mus; Pathogenesis; Pattern; Permeability; Phenotype; Play; Production; Property; Proteins; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Small Intestines; Stomach; Surface; Symptoms; Testing; Therapeutic Intervention; Tight Junctions; Tissues; Transgenic Mice; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; cytokine; dietary restriction; enteritis; eosinophil; eosinophil peroxidase; eosinophilic gastroenteritis; experience; gastrointestinal; human tissue; in vivo; intestinal epithelium; novel; occludin; overexpression; response; Adrenal Cortex Hormones; Affect; Allergic; Apical; Asthma; Atopic Dermatitis; Body Weight decreased; Cells; Clinical; Colon; Cytoplasmic Granules; Data; Deposition; Development; Diagnostic; Diagnostic tests; Diarrhea; Disease; Elements; Eosinophil Granule Proteins; Eosinophil cationic protein; Eosinophil-Derived Neurotoxin; Eosinophilia; Eosinophilic Colitis; Epithelial; Epithelial Cells; Epithelium; Esophagus; Food; Food Hypersensitivity; Functional disorder; Gastroesophageal reflux disease; Gastrointestinal tract structure; Gene Expression; Goals; Hemorrhage; Human; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-5; Intestines; Knockout Mice; Knowledge; Lamina Propria; Little' s Disease; Malabsorption Syndromes; Measures; Mediating; Microarray Analysis; Modeling; Molecular; Mucous Membrane; Mus; Pathogenesis; Pattern; Permeability; Phenotype; Play; Production; Property; Proteins; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Small Intestines; Stomach; Surface; Symptoms; Testing; Therapeutic Intervention; Tight Junctions; Tissues; Transgenic Mice; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; cytokine; dietary restriction; enteritis; eosinophil; eosinophil peroxidase; eosinophilic gastroenteritis; experience; gastrointestinal; human tissue; in vivo; intestinal epithelium; novel; occludin; overexpression; response

DESCRIPTION (provided by applicant): Food allergic diseases are both more commonly recognized and occurring with an increased incidence. Histological hallmarks of certain food allergic diseases, such as eosinophilic gastroenteritis (EOG), include mucosal eosinophilia and deposition of eosinophil derived granule proteins (EDGPs) in the affected tissues. The most studied of these unique biologically active proteins such as major basic protein (MBP). Despite a large body of evidence describing clinicopathological features of EOGs, the role of eosinophils in the pathogenesis of these diseases is yet to be determined. While EDGPs likely play a role in allergic diseases, little is known about molecular mechanisms that EDGPs induce functional responses. Our preliminary data identified MBP influences two functional aspects of the intestinal epithelium. First, MBP diminishes epithelial barrier function likely through its impact on the tight junctional proteins, specifically occludin. Second, several layers of evidence show that MBP can induce epithelial TNF secretion and that the induction of this pro-inflammatory cytokine leads to disruption of barrier function. In combination, these results are particularly important since EOG is associated with impaired barrier function and altered cytokine production. Therefore, we hypothesize that EDGPs contribute to the pathogenesis of EOG by inducing epithelial proinflammatory cytokine production and diminishing barrier function. We present three focused specific aims to test this hypothesis: 1) define the impact of EDGPs on epithelial cytokine expression, 2) determine the influence of EDGPs on epithelial tight junction protein regulation, 3). Define the relevance of EDGPs in EOG utilizing EDGP null and "overexpressing" mice. In addition, we will define barrier properties and immunophenotypic features of human tissues affected by EOG. Long-term goals of these studies are the identification of specific diagnostic tests for EOGs and the development of novel eosinophil specific treatments.

描述（由申请人提供）：食物过敏性疾病均更加常见，并且发生率增加。 某些食物过敏性疾病的组织学标志，例如嗜酸性胃肠炎（EOG），包括粘膜嗜酸性粒细胞和嗜酸性粒细胞衍生的颗粒蛋白（EDGP）的沉积。 这些独特的生物活性蛋白（例如主要碱性蛋白（MBP））中最受研究的最多的研究。 尽管有大量的证据描述了EOG的临床病理特征，但嗜酸性粒细胞在这些疾病的发病机理中的作用尚未确定。 尽管EDGP可能在过敏性疾病中起作用，但对EDGP诱导功能反应的分子机制知之甚少。 我们的初步数据确定MBP影响肠上皮的两个功能方面。 首先，MBP可能通过对紧密连接蛋白（特别是闭塞蛋白）的影响来降低上皮屏障功能。 其次，几层证据表明，MBP可以诱导上皮TNF分泌，并且这种促炎性细胞因子的诱导会导致屏障功能的破坏。 结合起来，这些结果尤其重要，因为EOG与屏障功能受损和细胞因子产生改变有关。 因此，我们假设EDGP通过诱导上皮促炎细胞因子的产生和屏障功能降低而导致EOG的发病机理。 我们提出了三个重点的特定目的，以检验这一假设：1）定义EDGP对上皮细胞因子表达的影响，2）确定EDGP对上皮紧密连接蛋白调节的影响，3）。 使用EDGP NULL和“过表达”小鼠定义EDGP在EOG中的相关性。 此外，我们将定义受EOG影响的人体组织的屏障特性和免疫表型特征。 这些研究的长期目标是鉴定EOG的特定诊断测试以及新型嗜酸性粒细胞特定治疗的发展。