BMP signaling in enteric nervous system development

应聘者描述(申请人提供)：应聘者是一名儿科外科医生，在发育生物学方面有很强的背景，计划研究肠道神经系统(ENS)发育的潜在机制，并阐明它可能如何解释儿童的肠道运动障碍。职业发展计划最初侧重于获得基本知识和实验技能，并通过参加课程作业和国家会议加以促进。未来几年的目标将是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项目，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。候选人的联合发起人W·艾伦·沃克博士和德鲁西拉·罗伯茨博士是拟议研究领域的资深研究人员，他们也投入了他们的科学专业知识和资源来推进这项申请的目标。马萨诸塞州总医院和哈佛医学院的制度环境为成功获得这一指导临床科学家发展奖提供了一个绝佳的机会。 这项拟议的研究重点放在ENS上，这是一种复杂的神经网络，对维持胃肠道功能至关重要。ENS由主要来自迷走神经脊细胞的神经元组成，迷走神经脊细胞以头尾移行的方式填充在肠道中。先天性巨结肠症是一种常见而严重的儿童肠梗阻原因，由神经元异常迁移引起，导致远端肠道无神经节细胞。在鸡胚胎中的初步证据表明，Bapx1或noggin的后肠靶向病毒错误表达抑制了信号分子BMP4的表达，并导致肠道无神经节细胞增多，暗示BMP信号在ENS的发育中起着重要作用。这项应用首先旨在充分描述这种新的先天性巨结肠症模型，并确定BMP信号在ENS发生中的作用。利用野生型和注射胚胎中分离的迷走神经脊神经和后肠进行器官培养实验，将进一步确定这些基因在ENS发育中的作用。最后，来自先天性巨结肠和其他先天性运动障碍患者的人体组织将通过原位杂交进行检测，以评估BMP信号在临床领域的重要性，从而增强对这些疾病的了解，并有助于完善儿童这些致残疾病的诊断和治疗。

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.