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: 9350313
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350313
• 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; 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; Modeling; Mucosal Immunity; Mus; Mutation; Neonatal; 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; immune function; immunoregulation; improved; insight; malformation; mortality; motility disorder; 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基本肠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。本提案的重点是通过肠神经系统发育和胃肠道粘膜免疫功能研究的指导阶段，扩大我在细胞生物学和神经免疫相互作用方面的背景，从而建立科学基础。指导临床科学家研究职业发展奖将为我提供受保护的时间，在肠神经系统和免疫系统发育领域进行培训，并研究它们在胃肠道粘膜免疫中的作用。我将由Ken Kudsk博士指导，他是肠道粘膜免疫学的世界专家，Miles Epstein博士是肠神经系统发育的世界专家，Will Burlingham博士是自身免疫、耐受性发展和淋巴细胞功能的世界专家，Chris Coe博士是发育和衰老过程中神经免疫调节的世界专家。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。Kudsk博士，导师团队和我自己制定的研究计划将大大有助于我作为一名独立研究人员的发展。我们将研究肠神经系统和胃肠道粘膜免疫之间的潜在发育联系。先天性巨结肠症（Hirschsprung's disease，HSCR）是一种先天性肠神经系统（enteric nervous system，ENS）节段性缺失的疾病，其病因是神经嵴细胞不能迁移到后肠远端，如果不及时治疗，往往是致命的。虽然HSCR可以 在接受无神经节肠节段性切除手术治疗的患者中，高达60%的患者在术前和术后发展为危及生命的先天性巨结肠相关性小肠结肠炎（HAEC），其病理生理学定义不清。我们已经在具有EdnrB的神经嵴特异性缺失（EdnrB-null）的动物中进行了初步研究，所述动物表现出远端结肠无神经节细胞症和密切的人类、新生儿HSCR模型。这些动物发展HAEC并在出生后第28天死亡。我们的初步研究结果表明，EdnrB基因敲除小鼠有较小的派尔集合淋巴结与较少的成熟B淋巴细胞比他们的杂合子同窝出生。此外，EdnrB缺失动物小肠分泌免疫球蛋白A（SIgA）的量减少，而SIgA是粘膜免疫防御的关键效应物.最后，胚胎组织的微阵列分析表明，在EdnrB基因敲除小鼠中，参与B淋巴细胞功能的基因表达降低。我们假设神经嵴中Ednr B的缺失导致神经嵴外内皮素表达改变和B淋巴细胞发育和/或功能缺陷，导致对HAEC的易感性增加。为了检验这一假设，我们将（目的1）确定在EdnrB神经嵴特异性缺失的动物中，内皮素轴在发育中的造血器官中的表达是否改变，（目的2）确定EdnrB神经嵴特异性缺失是否导致B淋巴细胞功能的内在或外在缺陷，和（目的3）确定生理应激对EdnrB-无效免疫表型的发展的贡献程度。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，将确保有一个更清晰的了解在HAEC的潜在机制和肠神经系统和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肠神经系统和胃肠道免疫系统在发育和疾病中的相互作用，以产生新的神经免疫调节疗法，这些疗法可能针对广泛的先天性和获得性儿科胃肠道疾病。