Engineering Novel Enteroid Models for Understanding Human Enteric Disease

 U19申请的总体描述（由申请人提供）：该申请要求资助德克萨斯州医学中心的NAMSED合作研究中心（简称CRC）。该CRC的主要目标将通过三个机构（贝勒医学院、莱斯大学、MD安德森癌症中心）的基础科学家、生物医学工程师和一名医生科学家组成的多学科综合团队的合作努力来实现。该CRC的总体目标是创建第一个具有生理活性并模拟人类肠道许多方面的离体微肠模型系统。我们将使用来自人类肠道活检的人类肠类（HIE）来解决由微生物引起的人类肠道疾病的关键问题，这些微生物引起人类肠道疾病，导致全球约4%的死亡。目前迫切需要能够充分反映相关人类生理学、病理生理学和自然宿主-病原体相互作用的新模型，因为大多数导致疟疾的人类病原体缺乏准确模拟人类疾病的动物模型。该CRC应用程序整合了一个具有多学科专业知识的团队，包括病毒学，细菌学（包括微生物组），基因组学，发育生物学和生理学，生物医学工程和工程组织的生物材料开发（包括体外血管化和3D打印），传染病流行病学和临床微生物学的基础和转化研究和创新。该CBC将包括3个项目和3个核心设施。项目1将使用高通量成像分析基因调控的宿主对人类轮状病毒和疫苗复制的限制，并确定导致病理生理学的上皮细胞反应。计划2 将使用HIEs来了解大肠杆菌感染的发病机制。包括急性和慢性感染、组织嗜性和病理机制之间差异的特征因子。项目3将结合联合收割机组织工程、生物材料设计和机械生物学，为HIE开发定制的生物功能平台，该平台可以被机械刺激，并将促进细胞和组织极性以及完整的隐窝绒毛分化，以促进肠道和肠道病原体的感染。这3个相互关联和协同作用的项目将得到3个核心设施的专业和智力贡献的支持：行政核心，人类肠道核心，基因组学和微生物组核心。两项发展研究先导计划将获资助，其中一项由教育署拨款资助。该CRC的成功取决于个体研究者和中心领导者的互补专业知识，他们是在指导互动，多学科项目方面经验丰富的高级科学家-管理人员。生物医学工程师、当地生物学家和其他NAMSED研究人员之间的合作和反复反馈将促进开发理想系统的进展，该系统将是最先进的，但对于传染病实验室的常规使用足够简单，对于临床前研究的使用足够稳健。

 DESCRIPTION OF THE OVERALL U19 APPLICATION (provided by applicant): This application requests funding of a NAMSED Cooperative Research Center (called CRC for simplicity) in the Texas Medical Center. This CRC's primary objective will be achieved through the collaborative efforts of a multidisciplinary, integrated team of basic scientists, biomedical engineers and a physician scientist who are at three institutions (Baylor College of Medicine (BCM), Rice University, the MD Anderson Cancer Center). The overall goal of this CRC is to create the first ex-vivo mini-gut model systems that are physiologically active and mimic many aspects of human intestine. We will use human intestinal enteroids (HIEs) derived from human intestinal biopsies to address key questions about human enteric disease caused by microorganisms that produce human diarrheal disease and lead to ~4% of all deaths worldwide. New models that adequately reflect relevant human physiology, pathophysiology and natural host-pathogen interactions are critically needed because most human pathogens that cause diarrheal disease lack animal models that accurately mimic the human disease. This CRC application integrates a team with multidisciplinary expertise including basic and translational research and innovation in virology, bacteriology including the microbiome, genomics, developmental biology and physiology, biomedical engineering and biomaterial development of engineered tissues including in vitro vascularization and 3D printing, infectious disease epidemiology and clinical microbiology. This CBC will consist of 3 Projects and 3 Core facilities. Project 1 will use HIEs to analyze genetically-regulated host restriction to human rotavirus and vaccine replication and to define epithelial cell responses that lead to pathophysiology. Project 2 will use HIEs to understand the pathogenesis of infections with diarrheagenic E. coli including factors that characterize differences between acute and chronic infections, tissue tropism and mechanisms of pathology. Project 3 will combine tissue engineering, biomaterial design, and mechanobiology to develop tailored, biofunctional platforms for HIEs that can be mechanically stimulated and that will promote cell and tissue polarity as well as the full crypt-villus differentiation to facilitate infection with commensals and enteropathogens. These 3 interrelated and synergistic projects will be supported by the specialized and intellectual contributions of 3 Core Facilities: the Administrative Core, Human Enteroid Core, and Genomics and Microbiome Core. Two Pilot Developmental Research Projects will be supported with one being funded by BCM. The success of this CRC depends on the complementary expertise of the individual investigators and center leaders who are senior scientists-administrators experienced in directing interactive, multidisciplinary programs. Collaboration and iterative feedback between biomedical engineers, local biologists and other NAMSED investigators will facilitate progress towards developing an ideal system that will be state of the art yet sufficiently simple for routin use in infectious disease laboratories and adequately robust for use in pre-clinical studies.