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Gastrointestinal Mucosal Immune Defects in Hirschsprungs Disease

先天性巨结肠症的胃肠粘膜免疫缺陷

基本信息

批准号：
9461521
负责人：
Ankush Gosain
金额：
$ 17.15万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9461521
关键词：
Accounting Affect Aging Anatomy Animals Anus Area Autoimmunity B-Cell Development B-Lymphocytes Biological Models Biological Process Birth Blood flow Cell Maturation Cell physiology Cellular biology Cessation of life Child Childhood Clinical Colonic Aganglionosis Colostomy Procedure Congenital Megacolon Defect Development Disease Distal Endothelin Endothelin B Receptor Endothelin-1 Ensure Enteric Nervous System Enterocolitis Etiology Excision Exhibits Failure Foundations Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Generations Goals Gut Mucosa Hematopoietic Heterozygote Hindgut Host Defense Human Immune Immune system Immunology Impairment Incidence Individual Inflammation Inherited Intestinal Atresia Intestinal Obstruction Intestines K-Series Research Career Programs Knockout Mice Knowledge Life Ligands Link Lymphocyte Function Malignant Neoplasms Mature B-Lymphocyte Mentors Mentorship Microarray Analysis Mucosal Immune System Mucosal Immunity Mucous Membrane Mus Mutation Neonatal Nervous System Physiology Neural Crest Neural Crest Cell Neuroimmune Neuroimmunomodulation Operative Surgical Procedures Organ Patients Phase Phenocopy Phenotype Physiological Population Postoperative Period Predisposition Prevention Quality of life Research Research Personnel Role Scientist Secretory Immunoglobulin A Signal Transduction Site Small Intestines Spleen Stress Structure of aggregated lymphoid follicle of small intestine Study models Systems Biology Systems Development Testing Time Tissues Training Transfection Water career development cell motility embryo tissue endothelin-3 receptor experience gastrointestinal human model immune function immunomodulatory therapies immunoregulation improved insight malformation mortality motility disorder nervous system development novel nutrient absorption public health relevance receptor renal agenesis theories trafficking

项目摘要

DESCRIPTION (provided by applicant): The ultimate translational goal of my research is to discover critical knowledge of basic enteric nervous system and gastrointestinal mucosal immune system biology that will improve the treatment and quality of life of children with acquired or inherited gastrointestinal disease. The focus of this proposal is to develop a scientific foundation by expanding upon my background in cell biology and neuro-immune interaction through a mentored phase of study of enteric nervous system development and gastrointestinal mucosal immune function. The Mentored Clinical Scientist Research Career Development Award will provide me with the protected time to train in the areas of enteric nervous system and immune system development and study their role in gastrointestinal mucosal immunity. I will be mentored by Dr. Ken Kudsk, a world expert in gut mucosal immunology, and Dr. Miles Epstein, a world expert in enteric nervous system development, Dr. Will Burlingham, a world expert in autoimmunity, development of tolerance, and lymphocyte function, and Dr. Chris Coe, a world expert in neuro-immunomodulation during development and aging. Each of these individuals has experience in mentoring young scientists and will guide me in my Career Development. The research plan crafted by Drs. Kudsk, the mentorship team, and myself will contribute substantially to my development as an independent researcher. We will investigate a potential developmental link between the enteric nervous system and gastrointestinal mucosal immunity. Hirschsprung's disease (HSCR) is a congenital segmental absence of the enteric nervous system (ENS) in the distal gut that results from failure of neural crest cell migration to the distal hindgut and is invariably lethal if untreated. Although HSCR can be surgically treated with segmental resection of the aganglionic bowel, up to 60% of patients in both the pre- and post-operative periods develop life-threatening Hirschsprung's-associated enterocolitis (HAEC), the pathophysiology of which is poorly defined. We have performed preliminary studies in animals with a neural crest-specific deletion of EdnrB (EdnrB-null) that exhibit distal colonic aganglionosis and closely model human, neonatal HSCR. These animals develop HAEC and die by post-natal day 28. Our preliminary results indicate that EdnrB-null mice have smaller Peyer's Patches with fewer mature B-lymphocytes than their heterozygote littermates. Additionally, the EdnrB- null animals have decreased amounts of small bowel secretory immunoglobulin A (SIgA), which is the key effector of mucosal immune defense. Finally, microarray analysis of embryonic tissue indicates decreased expression of genes involved in B-lymphocyte function in EdnrB-null mice. We hypothesize that deletion of EdnrB in the neural crest results in altered endothelin expression outside the neural crest and defective B- lymphocyte development and/or function, resulting in increased susceptibility to HAEC. In order to test this hypothesis, we will (Aim 1) determine if expression of the endothelin axis in developing hematopoietic organs is altered in animals with a neural crest-specific deletion of EdnrB, (Aim 2) determine if neural crest specific deletion of EdnrB results in intrinsic or extrinsc defects in B-lymphocyte function, and (Aim 3) determine the extent of the contribution of physiologic stress to the development of the EdnrB-null immune phenotype. We expect that these studies will provide insight into potential immunomodulatory targets for prevention and treatment of Hirschsprung's-associated enterocolitis. Completion of these aims ensures that there will be a clearer understanding of the underlying mechanisms in HAEC and the relationship between enteric nervous system and gastrointestinal mucosal immune development. The long-term goal of our research is to gain an understanding of the interactions between the enteric nervous system and gastrointestinal immune system in both development and disease to permit the generation of novel neuro-immunomodulatory therapies that may potentially target a broad range of congenital and acquired pediatric gastrointestinal tract diseases.

描述(申请人提供)：我的研究的最终翻译目标是发现基本的肠道神经系统和胃肠道粘膜免疫系统生物学的关键知识，这将改善获得性或遗传性胃肠道疾病儿童的治疗和生活质量。这项建议的重点是通过对肠道神经系统发育和胃肠道粘膜免疫功能的指导阶段的研究，通过扩展我在细胞生物学和神经免疫相互作用方面的背景，建立一个科学基础。导师临床科学家研究职业发展奖将为我提供有保障的时间，让我在肠道神经系统和免疫系统发展领域进行培训，并研究它们在胃肠道粘膜免疫中的作用。我将接受肠道粘膜免疫学世界专家Ken Kudsk博士、肠道神经系统发育世界专家Miles Epstein博士、自身免疫、耐受发展和淋巴细胞功能世界专家Will Burlingham博士以及发育和衰老期间神经免疫调节世界专家Chris Coe博士的指导。这些人中的每一个都有指导年轻科学家的经验，并将指导我的职业发展。由Kudsk博士、导师团队和我自己起草的研究计划将对我作为一名独立研究员的发展做出重大贡献。我们将调查肠道神经系统和胃肠道粘膜免疫之间潜在的发育联系。先天性巨结肠(HSCR)是一种先天性远端肠道内肠神经系统(ENS)的节段性缺失，是由于神经脊细胞未能迁移到远端后肠而导致的，如果不治疗，总是致命的。尽管HSCR可以在采用节段性无神经节段切除术治疗的患者中，高达60%的患者在手术前后都会发展为危及生命的先天性巨结肠相关性小肠结肠炎(HAEC)，其病理生理机制尚不明确。我们对EDNRB神经峰特异性缺失(EDNRB-空)的动物进行了初步研究，这些动物表现出远端结肠无神经节细胞增多症，并与人类、新生儿HSCR密切相关。这些动物会发展成HAEC，并在出生后第28天死亡。我们的初步结果表明，EDNRB缺失的小鼠比它们的杂合子小鼠有更小的Peyer‘s斑块，成熟B淋巴细胞更少。此外，EDNRB基因缺失的动物小肠分泌型免疫球蛋白A(SIgA)的数量减少，SIgA是粘膜免疫防御的关键效应器。最后，对胚胎组织的微阵列分析表明，在EDNRB基因缺失的小鼠中，涉及B淋巴细胞功能的基因表达减少。我们推测，EDNRB在神经峰缺失会导致神经峰外内皮素表达的改变和B淋巴细胞发育和/或功能的缺陷，从而增加对HAEC的易感性。为了验证这一假设，我们将(目标1)确定EDNRB神经峰特异性缺失的动物在发育中的造血器官中内皮素轴的表达是否发生变化，(目的2)确定神经峰特异性EDNRB缺失是否会导致B淋巴细胞功能的内在或外在缺陷，以及(目的3)确定生理应激对EDNRB缺失免疫表型发展的影响程度。我们期望这些研究将为预防和治疗先天性巨结肠相关性小肠结肠炎提供潜在的免疫调节靶点。这些目标的完成将确保对HAEC的潜在机制以及肠道神经系统和胃肠粘膜免疫发育之间的关系有更清晰的了解。我们研究的长期目标是了解肠道神经系统和胃肠道免疫系统在发育和疾病过程中的相互作用，以便产生新的神经免疫调节疗法，可能针对广泛的先天性和获得性儿科胃肠道疾病。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulin A production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.

先天性巨结肠相关小肠结肠炎神经嵴条件性删除内皮素受体 B 模型中分泌性免疫球蛋白 A 产生的 B 淋巴细胞内在和外在缺陷。

DOI：
10.1096/fj.201801913r
发表时间：
2019
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Medrano,Giuliana;Cailleux,Frederic;Guan,Peihong;Kuruvilla,Korah;Barlow-Anacker,AmandaJ;Gosain,Ankush
通讯作者：
Gosain,Ankush

Comprehensive selection of reference genes for quantitative RT-PCR analysis of murine extramedullary hematopoiesis during development.