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：
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
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/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

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（由申请人提供）：该赠款提案描述了一项为期5年的培训计划，以发展校长或（PI）作为独立的医生 - 科学家。芝加哥儿童医院（IL）由内部K奖与医生奖一起资助西北计划和班级。 Rocess，PI将招募一群具有指导K08的经验，而Barry Wershil，M.D。结肠炎（UC），一种炎症的肠道疾病（IBD），与您结肠癌分离，慢性腹痛和一些血腥的腹泻，这种疾病会影响结肠的儿童和成人l是唯一的治疗疗法医疗治疗，许多患者仍需要去除结肠或发病率。 IL6）介导的ER是IBD的药物，研究了肥大细胞衍生的介体在结肠炎中的作用和需求。 H4R是组胺的地窖来源，而H4R被激活以释放IL-6。结肠炎的最终目的是分析UC活检和对照组中H4R和IL-6的细胞表达。