Gastrointestinal Mucosal Immune Defects in Hirschsprungs Disease

先天性巨结肠症的胃肠粘膜免疫缺陷

• 批准号: 8878041
• 负责人: Ankush Gosain
• 金额: $ 15.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-23 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878041
• 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; Hematopoietic; Heterozygote; Hindgut; Host Defense; Human; Immune; Immune system; Immunology; 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; Modeling; Mucosal Immunity; Mus; Mutation; Nervous System Physiology; Neural Crest; Neural Crest Cell; 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; Work; career development; cell motility; embryo tissue; experience; gastrointestinal; immune function; immunoregulation; improved; insight; malformation; mortality; motility disorder; neonatal human; nervous system development; novel; nutrient absorption; public health relevance; receptor; renal agenesis; theories; trafficking

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（由申请人提供）：我的研究的最终转化目标是发现对基本肠神经系统和胃肠道粘膜免疫系统生物学的批判性知识，这将改善胃肠道或遗传性胃肠道疾病儿童的治疗和生活质量。该提案的重点是通过扩展我的细胞生物学和神经免疫相互作用的背景，通过对肠神经系统发育和胃肠道粘膜免疫功能进行指导的研究阶段来发展科学基础。指导的临床科学家研究职业发展奖将为我提供受保护的时间，以训练肠神经系统和免疫系统开发领域，并研究其在胃肠道粘膜免疫中的作用。我将受到肠道粘膜免疫学的世界专家肯·库兹克（Ken Kudsk）博士的指导，以及肠神经系统发展方面的世界专家迈尔斯·爱泼斯坦（Miles Epstein）博士威尔·伯林汉姆（Will Burlingham）博士是自身免疫性，耐受性发展和淋巴细胞功能的发展世界专家，以及在开发和敏捷期间的神经免疫性和敏捷性的世界专家克里斯·科（Chris Coe）博士。这些人都有指导年轻科学家的经验，并将指导我的职业发展。博士制定的研究计划。 Kudsk，指导团队和我本人将为我作为独立研究人员的发展做出基本贡献。我们将研究肠神经系统与胃肠道粘膜免疫之间的潜在发育联系。 Hirschsprung病（HSCR）是远端肠道内肠神经系统（ENS）的先天性节段性，是由于神经rest细胞迁移到远端后肠而导致的，如果未经治疗，则偶然地致死。虽然HSCR可以 在术前和术后的患者中，可以通过分段的剧明肠道切除术进行手术治疗，多达60％的患者发展了威胁生命的Hirschsprung相关性小肠结肠炎（HAEC），其病理生理学的定义较差。我们已经在具有神经克雷斯特特异性缺失的EDNRB（EDNRB-NULL）的动物中进行了初步研究，该研究表现出远端结肠aganglionisos，并密切模拟了人类新生儿HSCR。这些动物在第28天后发生HAEC并死亡。我们的初步结果表明，Ednrb-null小鼠的PEYER斑块较小，成熟的B淋巴细胞比其杂合子同窝仔。此外，EDNRB-NULL动物减少了小肠分泌免疫球蛋白A（SIGA），这是粘膜免疫防御的关键效应因子。最后，对胚胎组织的微阵列分析表明，EDNRB-NULL小鼠中涉及B淋巴细胞功能的基因表达降低。我们假设eDNRB在神经rest中的缺失导致内皮素的表达改变，而B-淋巴细胞发育和/或功能有缺陷，从而增加了对HAEC的敏感性。为了检验这一假设，我们将（目标1）确定在发展造血器官中的内皮素轴的表达是否在具有神经crest的特异性缺失EDNRB的动物中会改变（目标2）神经trest的神经tre虫是否确定EDNRB的特定特定的EDNRB的特定depinscy或Extrinsccy defection defection n defection n defection the b-extection n defection n of B-extects n of B-extects n of B-extects n of B-exters of b----功能界面的范围（范围）（ EDNRB-NULL免疫表型发育的生理压力。我们预计这些研究将为预防和治疗Hirschsprung相关的小肠结肠炎的潜在免疫调节靶标提供深入的了解。这些目的的完成确保了对HAEC的潜在机制以及肠神经系统与胃肠道粘膜免疫发育之间的关系。我们研究的长期目标是了解发育和疾病中肠道神经系统与胃肠道免疫系统之间的相互作用，以使新的神经免疫调节疗法产生，这些疗法可能有可能靶向广泛的先天性和获得的儿童胃肠道疾病。