Gastrointestinal Mucosal Immune Defects in Hirschsprungs Disease

描述（由申请人提供）：我研究的最终转化目标是发现基础肠神经系统和胃肠道粘膜免疫系统生物学的关键知识，从而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道神经系统发育和胃肠道粘膜免疫功能的指导阶段研究，扩展我在细胞生物学和神经免疫相互作用方面的背景，从而建立科学基础。导师临床科学家研究事业发展奖将为我提供受保护的时间，在肠道神经系统和免疫系统发育方面进行培训，研究它们在胃肠道粘膜免疫中的作用。我的导师是Ken Kudsk博士，世界肠道黏膜免疫学专家，Miles Epstein博士，世界肠道神经系统发育专家，will Burlingham博士，世界自身免疫，耐受性发展和淋巴细胞功能专家，以及Chris Coe博士，世界发育和衰老过程中神经免疫调节专家。他们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。研究计划是由dr。库德斯克、导师团队和我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道粘膜免疫之间的潜在发育联系。巨结肠病（HSCR）是一种远端肠道先天性节段性肠神经系统（ENS）缺失，由神经嵴细胞迁移到远端后肠失败引起，如果不治疗，总是致命的。尽管HSCR可以

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.