"Human in vivo model to study the role of a functional enteric nervous system on intestinal development and maturation"

“人体模型研究功能性肠神经系统对肠道发育和成熟的作用”

• 批准号: 9163325
• 负责人: Maxime Mickaël Mahe
• 金额: $ 9.12万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9163325
• 关键词: Affect; Applications Grants; Area; Behavior; Biological Models; Blood Vessels; Blood flow; Cell Differentiation process; Cell Proliferation; Complex; Congenital Megacolon; Data; Defect; Development; Digestive System Disorders; Disease; Doctor of Philosophy; Electrolytes; Enteral; Enteric Nervous System; Epithelial; Epithelial Cell Proliferation; Epithelium; Exhibits; Exposure to; Fecal Incontinence; France; Functional disorder; Future; Gastrointestinal Diseases; Gastrointestinal Motility; Genetic; Goals; Grant; Growth; Growth and Development function; Human; Intestinal Motility; Intestines; Irritable Bowel Syndrome; Knowledge; Lead; Lesion; Link; Maintenance; Marshal; Medical Research; Medical center; Medicine; Mentors; Mesenchymal; Methods; Michigan; Modeling; Molecular; Movement; Mus; Nerve; Nervous System control; Neuroglia; Neuropathy; Nutrient; Onset of illness; Organoids; Outcome Measure; Patients; Pediatric Hospitals; Peristalsis; Permeability; Phenotype; Pluripotent Stem Cells; Process; Reporting; Research; Role; Stem cells; System; Testing; Tissue Engineering; Tissues; Training; Transplantation; United States National Institutes of Health; Universities; Villus; Water; Work; Writing; absorption; base; career; cell motility; cell type; college; gastrointestinal; gastrointestinal function; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; interdisciplinary approach; intestinal epithelium; medical schools; microbiome; motility disorder; multidisciplinary; new technology; novel; repaired; response; skills

Project Summary Emerging data has identified the enteric nervous system (ENS) as a key regulator of intestinal barrier functions. Besides the control of peristaltic movements, gastrointestinal blood flow and secretions, the ENS has been shown to reinforce the intestinal epithelial barrier (IEB) and modulate intestinal permeability. Changes in ENS have largely been described in gastrointestinal diseases with altered IEB functions. However, the link between the molecular and cellular effects of the ENS on IEB lesions still remains elusive mainly due to the lack of models. In this context, the development of human intestine with an ENS represents a real opportunity to expand our knowledge into the effect of ENS on intestinal development and toward the understanding of pathophysiological processes leading to digestive diseases. Our recently developed methods to generate a functional human intestine, combined with unique transplantation models, provide a novel and ideal experimental approach. Building on this previous model, we generated a complex human intestine reassembling the ENS features to test the hypothesis that human ENS regulates intestinal development, growth, and maturation. This grant application brings another level of innovation to the GI organoid systems by tissue engineering in the enteric nervous system. This proposal has three major strands. Precisely, we will define the ENS mechanisms underlying human intestinal organoid development into a fully laminated and functional mature intestine (Aim 1). We will determine the influence of intestinal luminal contents on the ENS phenotype and its associated functions (Aim 2). Finally, we will characterize the impact of congenital defective ENS on the intestinal development that lead to gastrointestinal dysfunctions (Aim 3). This research plan will allow for unprecedented studies in the future of the molecular basis of human ENS control of GI functions and diseases. To successfully achieve the aforementioned goals, a multidisciplinary group of mentors, collaborators and consultants will provide guidance in the research strategy and other training areas such as grant writing, personal, technical and management skills. Additionally, I will get additional training and course work to succeed in the completion of the proposal and in my transition toward a successful independent scientific career. Mentors Pr Michael A. Helmrath, MD, MS - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Pr James M. Wells, PhD, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Collaborator Dr Michel Neunlist, PhD - National Institute of Health and Medical Research (INSERM) – Unit 913 Neuropathies of the Enteric Nervous System and Digestive Diseases, Nantes, France Consultants Pr. Marshall H. Montrose, PhD – University of Cincinnati, Cincinnati, OH, USA Dr. Ajay Kaul, MD - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Dr. Noah F. Shroyer, PhD – Baylor College of Medicine, Houston, TX, USA Referees Dr. Sean R. Moore, MD, MS - Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Dr. Jason Spence, PhD - University of Michigan Medical School, - Ann Harbor, MI, USA Dr. Yana Zavros, PhD - University of Cincinnati - Cincinnati, OH, USA

项目摘要 新兴数据已将肠神经系统（ENS）确定为肠屏障的关键调节剂 功能。除了控制蠕动运动，胃肠道血流和分泌物外 已证明可以增强肠上皮屏障（IEB）并调节肠道通透性。 ENS的变化在很大程度上描述了IEB功能改变的胃肠道疾病。然而， ENS对IEB病变的分子和细胞效应之间的联系仍然难以捉摸 缺乏模型。在这种情况下，人类肠道的开发代表了真实的 将我们的知识扩展到ENS对肠道发展和朝向的影响的机会 了解导致消化疾病的病理生理过程。我们最近开发的方法 为了产生功能性的人类肠，再加上独特的移植模型，提供了一种新颖的和 理想的实验方法。在以前的模型的基础上，我们产生了一个复杂的人类肠道 重新组装ENS特征，以检验人类ENS调节肠发展的假设， 生长和成熟。 该赠款应用程序通过组织工程为GI器官系统带来了另一个级别的创新 肠神经系统。该提议有三个主要链。确切地说，我们将定义ENS 人类肠道器官发育为完全层压和功能成熟的机制 肠道（目标1）。我们将确定肠道含量对ENS表型及其ITS的影响 关联功能（AIM 2）。最后，我们将表征先天性有缺陷的ENS对 导致胃肠道功能障碍的肠发展（AIM 3）。该研究计划将允许 未来对胃肠道功能和疾病的人类控制的分子基础的前所未有的研究。 为了成功实现优先考虑的目标，是一个多学科的导师，合作者和 顾问将在研究策略和其他培训领域（例如赠款写作）中提供指导 个人，技术和管理技能。此外，我将获得其他培训和课程工作 在提案的完成以及我向成功的独立科学的过渡中成功完成 职业。 导师 PR Michael A. Helmrath，医学博士，MS -Cincinnati儿童医院医疗中心，美国俄亥俄州，美国俄亥俄州 PR James M. Wells，辛辛那提儿童医院医疗中心，美国俄亥俄州俄亥俄州，美国俄亥俄州 合作者 Michel Neunlist博士，博士 - 国家卫生与医学研究所（INSERM） - 第913单元 肠神经系统和消化系统疾病的神经病，南特，法国 顾问 PR。马歇尔·H·蒙特罗斯（Marshall H. 医学博士Ajay Kaul博士 - 美国俄亥俄州辛辛那提市辛辛那提儿童医院医疗中心 美国德克萨斯州休斯敦市贝勒医学院博士Noah F. Shroyer博士 引用 MS医学博士Sean R. Moore博士-Cincinnati儿童医院医疗中心，美国俄亥俄州，美国俄亥俄州 Jason Spence博士，博士 - 密歇根大学医学院 - 美国密歇根州安港 Yana Zavros博士，博士 - 辛辛那提大学 - 俄亥俄州辛辛那提