Engineering Novel Enteroid Models for Understanding Human Enteric Disease

 U19整体申请说明(由申请人提供)：此申请申请为德克萨斯医学中心的NAMSED合作研究中心(简称CRC)提供资金。通过一个由基础科学家、生物医学工程师和三个机构(贝勒医学院(BCM)、莱斯大学、MD安德森癌症中心)的一名内科科学家组成的多学科综合团队的共同努力，这一合作研究中心的主要目标将得以实现。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体外迷你肠道模型系统。我们将使用从人类肠道活检中提取的人类肠类肠道(HIE)来解决由微生物引起的人类肠道疾病的关键问题，这些微生物会产生人类腹泻疾病，并导致全球约4%的死亡。迫切需要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，因为大多数导致腹泻疾病的人类病原体缺乏准确模拟人类疾病的动物模型。这一CRC应用整合了一支拥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(包括体外血管形成和3D打印)、传染病流行病学和临床微生物学方面的基础和翻译研究与创新。该中心将由3个项目和3个核心设施组成。项目1将使用HIE来分析受基因调控的宿主对人类轮状病毒和疫苗复制的限制，并定义导致病理生理学的上皮细胞反应。项目2 将使用HIE了解致泻性大肠杆菌感染的发病机制，包括表征急性和慢性感染之间的差异的因素、组织取向和病理机制。项目3将结合组织工程、生物材料设计和机械生物学为HIE开发量身定制的生物功能平台，这些平台可以被机械刺激，并将促进细胞和组织的极性以及充分的隐窝绒毛分化，以促进共生体和肠道病原体的感染。这3个相互关联和协同的项目将得到3个核心设施的专门和智力贡献的支持：行政核心、人类肠道核心以及基因组和微生物核心。两个试验性发展研究项目将得到支持，其中一个由BCM资助。这一合作研究的成功有赖于作为高级科学家的个人研究人员和中心领导的互补专业知识，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迭代反馈将促进朝着开发一种理想系统的进展，该系统将是最先进的，但足够简单，可用于传染病实验室的常规使用，并足够强大，可用于临床前研究。

 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.