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

基本信息

批准号：
9096090
负责人：
Joshua Brian Wechsler
金额：
$ 14.95万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/9096090
关键词：
Abdominal Pain Address Adult Affect Age Agonist Applications Grants Asthma Basophils Biology Biopsy Bone Marrow Cell Density Cell physiology Cells 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 tract structure Health 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 Receptor Interleukin-6 Intestines K-Series Research Career Programs Knockout Mice 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 receptor reconstitution response

项目摘要

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（由应用程序提供）：该赠款提案描述了一项为期5年的培训计划，以发展主要研究者（PI）为独立的身体科学家的学术生涯。 PI是芝加哥Ann＆Robert H. Lurie儿童医院（伊利诺伊州芝加哥）的董事会认证的小儿胃肠病医生，并获得了内部K奖，并努力研究了75％的研究，从而使职业发展成为身体科学家。在此提案期间，PI将继续转化研究活动以及职业发展通过西北大学的课程和课程。目前，PI的重点是研究肥大细胞在胃肠道（GI）炎症疾病中的作用。 PI看到患有炎症性胃肠道疾病的患者，例如溃疡性结肠炎和嗜酸性静脉炎。主要的心态是Paul Bryce副教授，博士学位，PI自2010年以来一直是Bryce博士实验室的产品成员。为了增强培训过程，PI将吸引一群具有巨大心理K08-授予者经验的院长。这包括罗伯特·施莱默（Robert Schleimer）博士。其在定义人类疾病中炎症机制方面的专业知识，以及两位身体科学家，医学博士Barry Wershil，小儿胃肠病学家，以及过敏症患者 - 免疫学家Bruce Bochner，均具有肥大细胞生物学的专业知识。这种环境将最大程度地提高PI在学术生涯中建立科学利基市场的潜力。该研究建议着重于溃疡性结肠炎（UC），一种炎症性肠病（IBD），分离为结肠，导致慢性腹痛和血液腹泻，最终导致结肠癌。这种疾病会影响儿童和成人，而去除结肠是唯一的治疗疗法。即使有最佳的医疗疗法，许多患者仍然需要去除结肠或发病率。仍然需要发现调节具有治疗潜力的疾病的新型途径。初步数据表明，通过下调白介素6（IL6）介导的结肠感染来阻止UC中的组胺4受体（H4R）可能是有益的。肥大细胞充当炎症介质的组织居民强力室，包括组胺和IL-6，后者是IBD中的药物靶标。该提案将调查肥大细胞衍生的介质在结肠炎中的作用和要求。中心假设是：肥大细胞通过H4R驱动IL-6介导的殖民炎症。尚未解决的机制的两个关键方面是组胺的细胞来源和H4R激活以释放IL-6的细胞。这两个问题将在三个目的中解决，前两个将分别解决肥大细胞衍生的组胺和IL-6的作用，利用肥大细胞缺陷小鼠的肥大细胞重构在结肠炎模型中的作用，最终目的是对H4R和IL-6在UC Biops和Controls中的细胞表达的分析。