BMP signaling in enteric nervous system development

描述（由申请人提供）：候选人是一名儿科外科医生，具有发育生物学的强大背景，计划研究肠神经系统（ENS）发育的潜在机制，并阐明它如何解释儿童肠道动力障碍。 职业发展计划最初侧重于获得基本知识和实验技能，并通过参加课程和国家会议提供便利。 后来的几年将致力于在马萨诸塞州总医院的儿科外科实验室内建立一个独立的研究工作，这一目标得到了该实验室主任兼儿科外科主任帕特里夏·多纳霍博士的大力支持。 候选人的共同赞助人W。Allan步行者和Drucilla Roberts博士是拟议研究领域的杰出研究人员，他们也致力于推进本申请的目标。 在马萨诸塞州总医院和哈佛医学院的制度环境提供了一个出色的机会，成功地追求这个指导临床科学家发展奖。 拟议的研究重点是ENS，这是一种维持胃肠道功能所必需的复杂神经网络。 ENS由主要由迷走神经嵴细胞产生的神经元组成，迷走神经嵴细胞以头尾向的迁移波填充肠。 先天性巨结肠症是一种常见的严重的小儿肠梗阻病因，它是由异常的神经元迁移引起的，导致远端肠无神经节细胞。 鸡胚中的初步证据表明，Bapx1或头蛋白的后肠靶向病毒错误表达抑制了信号分子BMP 4的表达，并导致肠道无神经节细胞症，暗示了BMP信号在ENS发育中的重要作用。 本申请的目的首先是充分表征这种新的先天性巨结肠模型，并建立BMP信号传导在ENS发育中的作用。 使用来自野生型和注射胚胎的分离的迷走神经嵴和后肠的器官培养实验将进一步确定这些基因在ENS发育中的作用。 最后，将通过原位杂交检查患有先天性巨结肠病和其他先天性运动障碍的患者的人体组织，以评估BMP信号在临床竞技场中的重要性，从而增强对这些疾病的理解，并帮助改进这些儿童致残性疾病的诊断和治疗。

DESCRIPTION (provided by applicant): The candidate is a pediatric surgeon with a strong background in developmental biology who plans to study the mechanisms underlying development of the enteric nervous system (ENS) and elucidate how it may explain disorders of intestinal motility in children. The career development plan focuses initially on acquiring basic knowledge and experimental skills, facilitated by participation in coursework and national meetings. The later years will be aimed at establishing an independent research effort within the Pediatric Surgical Laboratories at Massachusetts General Hospital, a goal strongly supported by Dr. Patricia Donahoe, director of that laboratory and chief of Pediatric Surgery. The candidate's co-sponsors, Dr. W. Allan Walker and Dr. Drucilla Roberts, accomplished investigators in the proposed field of study, have also committed their scientific expertise and resources to advancing the goals of this application. The institutional environment at Massachusetts General Hospital and Harvard Medical School provides an outstanding opportunity to successfully pursue this Mentored Clinical Scientist Development Award. The proposed research focuses on the ENS, a complex neuronal network essential for maintaining a functional gastrointestinal tract. The ENS is comprised of neurons arising primarily from vagal neural crest cells that populate the bowel in a craniocaudal wave of migration. Hirschsprung's disease, a common and severe cause of bowel obstruction in children, resulted from abnormal neuronal migration, leaving the distal bowel aganglionic. Preliminary evidence in chick embryos demonstrates that hindgut-targeted viral misexpression of Bapx1 or noggin inhibits expression of the signaling molecule BMP4 and leads to intestinal aganglionosis, implicating an essential role for BMP signaling in ENS development. This application first aims to fully characterize this novel model of Hirschsprung's disease and establish the role of BMP signaling in ENS development. Organ culture experiments using isolated vagal neural crest and hindgut from wild-type and injected embryos will further define the roles of these genes in ENS development. Finally, human tissue from patients with Hirschsprung's disease and other congenital motility disorders will be examined by in situ hybridization to assess the importance of BMP signaling in the clinical arena, thereby enhancing the understanding of these disorders and helping to refine the diagnosis and treatment of these disabling conditions in children.