Regulation of Ulcerative Colitis by mast cells and histamine

肥大细胞和组胺对溃疡性结肠炎的调节

• 批准号: 9351512
• 负责人: Joshua Brian Wechsler
• 金额: $ 16.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351512
• 关键词: Abdominal Pain; Address; Adult; Affect; Age; Agonist; Applications Grants; Asthma; Basophilic Cell; Biopsy; Bone Marrow; Cell Density; Cell physiology; Cells; Cellular biology; Chicago; Child; Childhood; Chronic; Clinical; Colectomy; Colitis; Colon; Colon Carcinoma; Color; Data; Dendritic Cells; Disease; Doctor of Medicine; Doctor of Philosophy; Drug Targeting; Environment; Eosinophilic Esophagitis; Epithelial Cells; Epithelium; Excision; Experimental Models; Female; Funding; Gastroenterologist; Gastrointestinal Diseases; Gastrointestinal tract structure; Hemorrhagic colitis; Histamine; Histamine Receptor; Histamine Release; Histologic; Human; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Immunologist; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interleukin 4 Receptor; Interleukin-6; Intestines; K-Series Research Career Programs; Knockout Mice; L Cells; Laboratories; Lipopolysaccharides; Mediating; Mediator of activation protein; Medical; Mentors; Modeling; Molecular Profiling; Morbidity - disease rate; Mucosal Immune Responses; Mucous Membrane; Mus; Newly Diagnosed; Oxazolone; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric Hospitals; Physicians; Play; Principal Investigator; Process; Production; Proteins; RNA; Receptor Activation; Regulation; Relapse; Research; Research Activity; Research Proposals; Rheumatoid Arthritis; Role; Scientist; Series; Severity of illness; Signal Transduction; Source; Stimulus; Symptoms; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Training Programs; Translational Research; Ulcerative Colitis; Universities; Up-Regulation; autocrine; cancer risk; career; career development; cellular imaging; chronic abdominal pain; curative treatments; cytokine; experience; gastrointestinal; human disease; male; mast cell; member; microbial; mid-career faculty; mouse model; novel; programs; public health relevance; receptor; reconstitution; response

 DESCRIPTION (provided by applicant): This grant proposal describes a 5-year training program to develop the academic career of the principal investigator (PI) as an independent physician-scientist. The PI is a board-certified pediatric gastroenterologist at Ann & Robert H. Lurie Children's Hospital of Chicago (Chicago, IL) funded by an internal K award with a 75% effort for research allowing for career development as a physician-scientist. During the period of this proposal, the PI will continue translational research activities along with career development through Northwestern University programs and classes. Currently the PI is focused on studying the role of mast cells in inflammatory diseases of the gastrointestinal (GI) tract. The PI sees patients with inflammatory GI illnesses such as ulcerative colitis and eosinophilic esophagitis as well. The primary mentor is Associate Professor Paul Bryce, Ph.D., and the PI has remained a productive member of Dr. Bryce's laboratory since 2010. To enhance the training process, the PI will enlist a group of co- mentors with significant experience mentoring K08-awardees. This includes Robert Schleimer, Ph.D. whose has expertise in defining mechanisms of inflammation in human diseases, and two physician-scientists, Barry Wershil, M.D. a pediatric gastroenterologist, and Bruce Bochner, MD, an allergist-immunologist, both with an expertise in mast cell biology. This environment will maximize the potential for the PI to establish a scientifi niche for an academic career. The research proposal focuses on ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), isolated to the colon, which causes chronic abdominal pain and bloody diarrhea, and ultimately, colon cancer. This disease affects both children and adults, and removal of the colon is the only curative therapy. Even with optimal medical therapy, many patients still require colon removal or suffer morbidity. Thus there remains a need to discover novel pathways that regulate the disease that offer therapeutic potential. The preliminary data suggests it may be beneficial to block the histamine 4-receptor (H4R) in UC by down-regulating interleukin-6 (IL6) mediated colonic inflammation. Mast cells function as tissue-resident powerhouses of inflammatory mediators, including histamine and IL-6, the latter of which is a drug target in IBD. This proposal will investigate the role and requirement of mast cell-derived mediators in colitis. The central hypothesis is: mast cells drive IL- 6 mediated colonic inflammation in UC via H4R. Two key aspects of the mechanism that remain unanswered are the cellular source of histamine and the cell in which H4R is activated to release IL-6. These two questions will be addressed in three aims, the first two will separately address the roles of mast cell-derived histamine and IL-6 utilizing mast cell reconstitution of mast cell-deficient mice in models of colitis, and the final aim is an analysis of cellular expression of H4R and IL-6 in UC biopsies and controls.

 描述（由申请人提供）：该资助计划描述了一个为期5年的培训计划，以发展主要研究者（PI）作为独立的医生科学家的学术生涯。PI是Ann & Robert H.的一名委员会认证的儿科胃肠病学家。Lurie儿童医院芝加哥（芝加哥，IL）由内部K奖资助，75%的努力用于研究，允许作为医生科学家的职业发展。在此建议期间，PI将继续开展转化研究活动，沿着职业发展 通过西北大学的课程和课程。目前，PI专注于研究肥大细胞在胃肠道（GI）炎症性疾病中的作用。PI也观察患有炎症性胃肠道疾病的患者，如溃疡性结肠炎和嗜酸性粒细胞性食管炎。 主要导师是副教授保罗布莱斯，博士，自2010年以来，PI一直是布莱斯博士实验室的富有成效的成员。为了加强培训过程，PI将招募一组具有指导K 08获奖者丰富经验的共同导师。其中包括Robert Schleimer博士。他在人类疾病中炎症机制的定义方面有专业知识，还有两名医生-科学家，巴里·韦希尔，医学博士。儿科胃肠病学家和医学博士布鲁斯博奇纳，过敏症免疫学家，都具有肥大细胞生物学的专业知识。这种环境将最大限度地发挥PI为学术生涯建立科学利基的潜力。 该研究计划的重点是溃疡性结肠炎（UC），一种炎症性肠病（IBD），孤立于结肠，导致慢性腹痛和血性腹泻，最终导致结肠癌。这种疾病影响儿童和成人，切除结肠是唯一的治疗方法。即使有最佳的药物治疗，许多患者仍然需要结肠切除或遭受发病。因此，仍然需要发现提供治疗潜力的调节疾病的新途径。初步数据表明，通过下调白细胞介素6（IL 6）介导的结肠炎症，阻断组胺4受体（H4 R）可能是有益的。肥大细胞作为炎症介质的组织驻留动力室，包括组胺和IL-6，后者是IBD的药物靶点。本研究将探讨肥大细胞源性介质在结肠炎中的作用和需求。中心假设是：肥大细胞通过H4 R驱动UC中IL- 6介导的结肠炎症。该机制的两个关键方面仍然没有答案，即组胺的细胞来源和H4 R被激活释放IL-6的细胞。这两个问题将在三个目标中解决，前两个将分别解决肥大细胞来源的组胺和IL-6在结肠炎模型中利用肥大细胞缺陷小鼠的肥大细胞重建的作用，最终目标是分析UC活检和对照中H4 R和IL-6的细胞表达。