Immune Control of Giardia Pathogenesis

贾第鞭毛虫发病机制的免疫控制

• 批准号: 8101513
• 负责人: STEVEN M SINGER
• 金额: $ 46.05万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101513
• 关键词: Actins; Acute; Adaptor Signaling Protein; Affect; Antibodies; Area; Biological Assay; C57BL/6 Mouse; CD8B1 gene; Categories; Celiac Disease; Cell Line; Cell membrane; Child; Cognitive; Complex; Cytoskeleton; Data; Defect; Development; Diarrhea; Disaccharidases; Disease; Enterocytes; Epithelial Cells; Experimental Models; Failure to Thrive; Flow Cytometry; Giardia; Giardia lamblia; Giardiasis; Human; Immune; Immune response; Immunity; Immunohistochemistry; In Vitro; Infection; Inflammatory Bowel Diseases; Intervention; Intestines; Kinetics; Knockout Mice; Lead; Link; Malabsorption Syndromes; Measures; Mediating; Microfilaments; Molecular; Mus; Muscle Cramp; Neoplasm Metastasis; Nutrient; Outcome; Parasites; Pathogenesis; Pathology; Pathway interactions; Phosphorylation; Post-Translational Regulation; Prevention; Process; Protein Dephosphorylation; Protein phosphatase; Proteins; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Surface; Symptoms; Syndrome; T cell response; T-Lymphocyte; Testing; Time; Vaccines; Virulence Factors; Vomiting; Western Blotting; Wild Type Mouse; absorption; biodefense; cellular microvillus; combat; crosslink; ezrin; genetic inhibitor; improved; in vitro Model; in vivo Model; intestinal epithelium; prevent; response; tumor; vaccine development

DESCRIPTION (provided by applicant): Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide resulting in nutrient malabsorption which can lead to cognitive developmental defects in children. Mechanisms of pathogenesis in giardiasis are poorly understood, hindering efforts to both treat and prevent this disease. Data suggest that immune responses contribute to pathology by inducing shortening of the microvilli on intestinal epithelial cells that provide an enhanced surface area for nutrient absorption. Our hypothesis is that immune responses affect the epithelial cell cytoskeleton through post-translational regulation of the adaptor protein ezrin. Ezrin links the plasma membrane to actin microfilaments and is essential for proper formation of microvilli. This proposal will test determine if immune responses against the parasite lead to changes in the function of ezrin in epithelial cells using mouse and in vitro models. The role of key signaling pathways and the ability to modulate these pathways with pharmacologicals will also be investigated. PUBLIC HEALTH RELEVANCE: Giardia is the most common protozoan cause of diarrhea in the US and is also considered a Biodefense Category B threat agent. The studies in this proposal will improve public health by examining how this infection causes nutrient malabsorption that can lead to defects in cognitive development. This information will provide new strategies for treating common diseases like celiac disease and inflammatory bowel disease as well as diarrheal diseases like giardiasis.

描述（由申请方提供）：贾第鞭毛虫是世界上最常见的引起腹泻的原生动物。它感染了全球约5亿人，导致营养吸收不良，可导致儿童认知发育缺陷。贾第虫病的发病机制知之甚少，阻碍了治疗和预防这种疾病的努力。数据表明，免疫应答通过诱导肠上皮细胞上的微绒毛缩短而促成病理，所述微绒毛提供增强的营养吸收表面积。我们的假设是，免疫反应影响上皮细胞的细胞骨架通过翻译后调节衔接蛋白ezrin。埃兹蛋白将质膜与肌动蛋白微丝连接起来，对微绒毛的正确形成至关重要。该提案将使用小鼠和体外模型测试确定针对寄生虫的免疫反应是否导致上皮细胞中ezrin功能的变化。还将研究关键信号通路的作用和用药理学调节这些通路的能力。 公共卫生相关性：贾第虫是美国最常见的引起腹泻的原生动物，也被认为是生物防御B类威胁因子。这项提案中的研究将通过检查这种感染如何导致营养吸收不良，从而改善公众健康，这种营养吸收不良可能导致认知发育缺陷。这些信息将为治疗常见疾病如乳糜泻和炎症性肠病以及肠道疾病如贾第虫病提供新的策略。