Role of the Pro-inflammatory MIF Homolog of Entamoeba histolytica in Colitis

溶组织内阿米巴促炎 MIF 同源物在结肠炎中的作用

• 批准号: 9278100
• 负责人: Shannon Moonah
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278100
• 关键词: Advisory Committees; Amebic colitis; Antibodies; Antibody titer measurement; Attenuated; Bangladeshi; Biological Assay; Birth; CRISPR/Cas technology; Cause of Death; Cells; Child; Colitis; Communicable Diseases; Data; Detection; Development Plans; Diarrhea; Disease; Entamoeba histolytica; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Exhibits; Feces; Funding; Genes; Genome; Goals; Histopathology; Homologous Gene; Human; IL8 gene; Immune; Immunity; Immunize; Immunoglobulin A; Immunoglobulin G; Immunology; Immunotherapy; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-6; Intestinal Mucosa; Intestinal Secretions; Intestines; Invaded; Investigation; Knowledge; Laboratories; Measures; Mediating; Mediator of activation protein; Mentors; Migration Inhibitory Factor; Mucositis; Mucous Membrane; Mus; Neutrophil Infiltration; Nitroimidazoles; Parasites; Pathogenesis; Pharmaceutical Preparations; Pneumonia; Production; Property; Quantitative Reverse Transcriptase PCR; Recombinants; Recruitment Activity; Research; Role; Scientist; Serum; Site; Small Interfering RNA; Statistical Data Interpretation; Surface; TNF gene; Techniques; Testing; Time; Tissues; Training; Translating; United States National Institutes of Health; Universities; Vaccination; Vaccines; Virginia; Work; career development; cohort; collaborative environment; cytokine; fluorescein isothiocyanate dextran; immunopathology; immunoregulation; in vivo; innovation; interleukin-23; killings; knock-down; macrophage; monocyte; mouse model; neutralizing antibody; novel; novel strategies; pathogen; phenylpyruvate tautomerase; prevent; programs; receptor; success; symposium; vaccination strategy

Project Summary Approach: We propose to test the hypothesis that the Entamoeba histolytica homolog of the upstream proinflammatory cytokine macrophage migration inhibitory factor (EhMIF) mediates a destructive inflammatory response in amebic colitis. We further hypothesize that EhMIF induces IL-8 production from intestinal epithelial cells resulting in recruitment of inflammatory cells to the intestinal mucosa. Additionally, we predict that EhMIF stimulates inflammatory cells in the intestinal mucosa resulting in excess TNF-α, IL-6 and IL-23 that disrupt the mucosal barrier. Innovative aspects of the proposal include that it explores a potentially novel mediator of parasite-induced injury at an understudied tissue site: the effect of parasite MIF homologs on intestinal mucosal inflammation and injury during infection is not known, and challenges the dominant paradigm that intestinal mucosal injury is a result of direct killing of host cells by E. histolytica. Successful completion of these studies will advance our understanding of the host-E. histolytica interactions and may translate into new approaches to immune-modulating therapies and vaccination. Significance: The work is significant because diarrheal disease is the second leading cause of death in children under five globally, and intestinal amebiasis is one of the main causes of severe diarrhea in the developing world. There currently exists no vaccine and only a single class of drugs, the nitroimidazoles, to treat this devastating disease. The environment for the work includes the superb academic infectious diseases program of the University of Virginia, a program of active investigation of E. histolytica in humans, murine models, and at the cellular level, and my mentor (Dr. Petri) who like myself is an infectious diseases clinician, and who has contributed to amebic colitis research for over 25 years. K08: My career development plan in this proposal will augment the success of this project through the combination of strong guidance and support from my internal and external advisory teams, courses, technical training, seminars and conferences focusing on immunology and host-pathogen interactions, all of which will help establish me as an independent clinician-scientist.

项目摘要 方法：我们建议测试的假设，溶组织内阿米巴同源物的上游 促炎细胞因子巨噬细胞移动抑制因子（EhMIF）介导破坏性炎症反应， 阿米巴结肠炎的反应。我们进一步假设EhMIF诱导肠上皮细胞产生IL-8， 上皮细胞导致炎性细胞向肠粘膜的募集。此外，我们预测 EhMIF刺激肠粘膜中的炎性细胞，导致过量的TNF-α、IL-6和IL-23 破坏粘膜屏障 该提案的创新方面包括，它探索了一种潜在的寄生虫诱导的新介质， 未充分研究的组织部位的损伤：寄生虫MIF同源物对肠粘膜炎症的影响 感染期间的损伤是未知的，并挑战了肠粘膜损伤是 这是E.溶组织剂 这些研究的成功完成将促进我们对宿主-E的理解。溶组织相互作用 并可能转化为免疫调节疗法和疫苗接种的新方法。 意义：这项工作意义重大，因为疟疾是世界上第二大死亡原因。 肠道阿米巴病是全球五岁以下儿童严重腹泻的主要原因之一， 发展中国家的团结合作目前还没有疫苗，只有一类药物，硝基咪唑， 治疗这种毁灭性的疾病。 工作环境包括大学一流的学术传染病项目 弗吉尼亚州，一个积极的调查计划，E。在人类、鼠模型中，以及在细胞中， 我的导师（Petri博士）和我一样是一名传染病临床医生，他为我的研究做出了贡献。 从事阿米巴结肠炎研究超过25年 K 08：我在本建议书中的职业发展计划将通过以下方式促进本项目的成功： 我的内部和外部咨询团队、课程、技术 以免疫学和宿主-病原体相互作用为重点的培训、研讨会和会议， 帮助我成为一名独立的临床科学家