BMP signaling in enteric nervous system development

描述（由申请人提供）：该候选人是一名儿科外科医生，在发育生物学方面有很强的背景，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运动障碍。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加以促进。今后几年的目标是在麻省总医院的儿科外科实验室内建立一个独立的研究机构，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。候选人的共同发起人，W. Allan Walker博士和Drucilla Roberts博士，在拟议的研究领域有成就的研究者，也承诺他们的科学专业知识和资源来推进这一申请的目标。麻省总医院和哈佛医学院的机构环境为成功获得指导临床科学家发展奖提供了绝佳的机会。

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.