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粘膜免疫系统生物学的关键知识，这将改善患有获得性或遗传性胃肠道疾病的儿童的治疗和生活质量。该提案的重点是通过肠神经系统发育和胃肠粘膜免疫功能研究的指导阶段，扩展我在细胞生物学和神经免疫相互作用方面的背景，从而奠定科学基础。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来进行肠神经系统和免疫系统发育领域的培训，并研究它们在胃肠道粘膜免疫中的作用。我将得到肠粘膜免疫学世界专家 Ken Kudsk 博士、肠神经系统发育世界专家 Miles Epstein 博士、自身免疫、耐受性发展和淋巴细胞世界专家 Will Burlingham 博士的指导。功能，以及发育和衰老过程中神经免疫调节方面的世界专家 Chris Coe 博士。这些人中的每个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。库德斯克、导师团队和我本人将为我作为一名独立研究员的发展做出重大贡献。我们将研究肠神经系统和胃肠粘膜免疫之间潜在的发育联系。先天性巨结肠症 (HSCR) 是一种远端肠道先天性节段性肠神经系统 (ENS) 缺失，由神经嵴细胞迁移至远端后肠失败所致，如果不治疗，必然致命。虽然 HSCR 可以 如果采用节段性无神经节肠切除术进行治疗，高达 60% 的患者在术前和术后都会出现危及生命的先天性巨结肠相关小肠结肠炎 (HAEC)，其病理生理学尚不清楚。我们对具有神经嵴特异性 EdnrB 缺失（EdnrB-null）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病，并且与人类新生儿 HSCR 密切相关。这些动物出现 HAEC 并在出生后第 28 天死亡。我们的初步结果表明，与杂合子同窝小鼠相比，EdnrB 缺失小鼠的派尔氏淋巴结更小，成熟 B 淋巴细胞更少。此外，EdnrB 缺失的动物的小肠分泌性免疫球蛋白 A (SIgA) 数量减少，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，EdnrB 缺失小鼠中涉及 B 淋巴细胞功能的基因表达降低。我们假设神经嵴中 EdnrB 的缺失会导致神经嵴外内皮素表达的改变以及 B 淋巴细胞发育和/或功能的缺陷，从而导致对 HAEC 的易感性增加。为了检验这一假设，我们将（目标 1）确定在神经嵴特异性删除 EdnrB 的动物中，发育中的造血器官中内皮素轴的表达是否发生改变，（目标 2）确定神经嵴特异性删除 EdnrB 是否会改变导致 B 淋巴细胞功能的内在或外在缺陷，并且（目标 3）确定生理应激对 EdnrB 无效免疫发展的贡献程度表型。我们期望这些研究将为预防和治疗先天性巨结肠相关小肠结肠炎的潜在免疫调节靶点提供见解。完成这些目标可以确保人们对HAEC的潜在机制以及肠神经系统和胃肠道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，以产生可能针对广泛的先天性和疾病的新型神经免疫调节疗法。后天性小儿胃肠道疾病。