Paneth cell dysfunction and gut dysbiosis in experimental intestinal inflammation

实验性肠道炎症中的潘氏细胞功能障碍和肠道生态失调

• 批准号: 8711435
• 负责人: Ajay S Gulati
• 金额: $ 15.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711435
• 关键词: Absenteeism at work; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Bacteria; Basic Science; Biological Assay; Biology; Cell physiology; Cells; Cellular Morphology; Cellular biology; Childhood; Chronic; Clinical Sciences; Colitis; Communities; Comorbidity; Complement; Complex; Computational Biology; Crohn' s disease; Data; Development; Disease; Ecology; Elements; Environment; Epithelial; Equilibrium; Exhibits; Family; Fostering; Foundations; Functional disorder; Funding; Future; Gastroenterologist; Gastrointestinal tract structure; Genes; Germ-Free; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Health Care Costs; Healthcare; Homologous Gene; Hospitalization; Host resistance; Human; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Institutes; Institution; Integration Host Factors; Interleukin-10; Intestinal Diseases; Intestines; Investigation; Laboratories; Lead; Learning; Ligands; Link; Measures; Mentorship; Muramidase; Mus; North Carolina; Operative Surgical Procedures; Organism; Paneth Cells; Pathogenesis; Patients; Physicians; Play; Positioning Attribute; Preventive; Proteins; Public Health; Publications; Quality of life; Relative (related person); Research; Research Methodology; Research Personnel; Research Training; Role; Schools; Scientist; Sequence Analysis; Sodium Dextran Sulfate; Statistical Models; Surface; Techniques; Testing; Therapeutic; Training; Transcript; Translational Research; United States; United States National Institutes of Health; Universities; Wild Type Mouse; antimicrobial; antimicrobial peptide; base; career; career development; commensal microbes; deep sequencing; design; disorder risk; gastrointestinal; gut microbiota; innovation; intestinal crypt; member; microbial; microbial community; microbicide; microorganism interaction; mouse model; new therapeutic target; novel; planetary Atmosphere; prevent; rRNA Genes; risk variant; skills; tool

DESCRIPTION (provided by applicant): The candidate is a pediatric gastroenterologist with a strong background in fundamental basic science research methods, and an established commitment to apply these skills to the study of inflammatory bowel diseases (IBD). The objective of the current K08 proposal is to obtain the advanced mechanistic training required to achieve the candidate's long-term career goal of becoming an independently funded physician- scientist, leading a laboratory focused on developing novel, minimally-toxic IBD therapies. Specifically, the candidate's short-term goals of this proposal are: 1) to acquire expertise in the study of host-microbial interactions, including the tools needed to ask mechanistic questions regarding these interactions; 2) to learn the fundamental principles of microbial ecology, including the techniques required to study complex gut microbial communities; and 3) to establish an area of independent research by generating a critical mass of data and publications that will support future NIH grant submissions. The candidate's overall research goal is to understand the mechanisms by which host epithelial dysfunction promotes bacterial imbalances in IBD patients. The objective of the current proposal is to understand the role of a specific intestinal epithelial subtype, the Paneth cell, in the development of experimental intestinal inflammation. The candidate hypothesizes that impaired Paneth cell antimicrobial activity is associated with pro-inflammatory changes of the gut microbiota that predispose to the development of intestinal inflammation. This hypothesis will be tested using a novel mouse model of intestinal inflammation deficient for the gene Immunity-related GTPase family M member 1 (Irgm1). In Aim 1, alterations of Paneth cell microbicidal function will be characterized using standard techniques, as well as innovative ex vivo assays focused on elucidating mechanisms of Paneth cell dysfunction. In Aim 2, pro-inflammatory alterations of the Irgm1-/- intestinal microbiota will be characterized through global profiling techniques and novel functional assays. These aims support the candidate's career development by providing training in mechanistic aspects of epithelial biology, as well as the study of complex microbial communities. Additional key elements of the candidate's training plan include: 1) advanced coursework in computational biology, sequence analysis, and statistical modeling; 2) a mentorship and advising team, which includes internationally-recognized, independently-funded investigators with expertise in host-microbial interactions, Paneth cell biology, and microbial ecology; and 3) scholarly activities designed to foster independence and national recognition. Finally, the candidate's research environment is based in a pre- eminent academic research institution (the University of North Carolina at Chapel Hill) with access to NIH- funded centers (including the Translational and Clinical Sciences Institute and Center for Gastrointestinal Biology and Disease) that are tailored to support the proposed studies. This environment will provide a productive and collaborative atmosphere in which to accomplish the described research and training goals.

描述（由申请人提供）：候选人是一名儿科胃肠病学家，在基础科学研究方法方面拥有深厚的背景，并致力于将这些技能应用于炎症性肠病（IBD）的研究。当前 K08 提案的目标是获得实现候选人长期职业目标所需的高级机械培训，即成为一名独立资助的医师科学家，领导一个专注于开发新型、毒性最小的 IBD 疗法的实验室。具体来说，该提案的候选人的短期目标是：1）获得以下领域的专业知识： 研究宿主-微生物相互作用，包括提出有关这些相互作用的机械问题所需的工具； 2）学习微生物生态学的基本原理，包括研究复杂肠道微生物群落所需的技术； 3) 通过生成大量数据和出版物来建立一个独立研究领域，以支持未来 NIH 拨款的提交。该候选人的总体研究目标是了解宿主上皮功能障碍促进 IBD 患者细菌失衡的机制。当前提案的目的是了解特定肠上皮亚型潘氏细胞在实验性肠道炎症发展中的作用。该候选人假设潘氏细胞抗菌活性受损与肠道微生物群的促炎变化有关，而肠道微生物群易于发生肠道炎症。该假设将使用免疫相关 GTP 酶家族 M 成员 1 (Irgm1) 基因缺陷的新型肠道炎症小鼠模型进行测试。在目标 1 中，将使用标准技术以及专注于阐明潘氏细胞功能障碍机制的创新离体测定来表征潘氏细胞杀菌功能的改变。在目标 2 中，将通过整体分析技术和新颖的功能测定来表征 Irgm1-/- 肠道微生物群的促炎改变。这些目标通过提供上皮生物学机械方面的培训以及复杂微生物群落的研究来支持候选人的职业发展。候选人培训计划的其他关键要素包括：1）计算生物学、序列分析和统计建模方面的高级课程； 2) 指导和咨询团队，其中包括国际公认的、独立资助的研究人员，他们在宿主-微生物相互作用、潘氏细胞生物学和微生物生态学方面具有专业知识； 3）旨在促进独立和国家认可的学术活动。最后，候选人的研究环境基于杰出的学术研究机构（北卡罗来纳大学教堂山分校），可以使用 NIH 资助的中心（包括转化和临床科学研究所以及胃肠生物学和疾病中心），这些中心是为支持拟议的研究而量身定制的。这种环境将提供高效和协作的氛围，以实现所描述的研究和培训目标。