Engineering Novel Enteroid Models for Understanding Human Enteric Disease

工程新肠模型用于了解人类肠道疾病

• 批准号: 8855931
• 负责人: Mary Kolb Estes
• 金额: $ 103.2万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8855931
• 关键词: 3D Print; Acute; Address; Administrator; Animal Model; Award; Bacteria; Bacteriology; Basic Science; Biocompatible Materials; Biological Models; Biomedical Engineering; Biopsy; Cancer Center; Cells; Cessation of life; Chronic; Clinical; Clinical Microbiology; Collaborations; Communicable Diseases; Communities; Complement; Complex; Core Facility; Dehydration; Development; Developmental Biology; Diarrhea; Disease; Engineering; Enteral; Epithelial; Epithelial Cells; Escherichia coli; Feedback; Food; Functional disorder; Funding; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Human; Immune; In Vitro; Individual; Infection; Infectious Disease Epidemiology; Infectious Diseases Research; Ingestion; Institution; Intestinal Diseases; Intestines; Kidney; Knowledge; Lead; Life; Medical center; Medicine; Mesenchymal; Microbe; Modeling; Molecular; Organism; Outcome; Pathogenesis; Pathology; Pathway interactions; Physicians; Physiology; Pilot Projects; Population Heterogeneity; Predisposition; Probiotics; Productivity; Property; Reproducibility; Request for Applications; Research; Research Personnel; Research Project Grants; Resources; Rice; Rotavirus; Rotavirus Vaccines; Scientist; Senior Scientist; Services; Stretching; System; Testing; Texas; Tissue Engineering; Tissues; Translational Research; Universities; Vascularization; Villus; Virus; Vomiting; Water; Work; biomaterial development; cell type; college; cost; design; expectation; experience; genetic manipulation; human disease; improved; in vivo Model; innovation; meetings; microbial host; microbiome; microorganism; multidisciplinary; new technology; novel; novel strategies; pathogen; pathogenic bacteria; preclinical study; prevent; programs; public health relevance; response; success; synergism; technology development; tissue tropism; virology

 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.

 整体U19申请的描述（由应用程序提供）：本申请要求在德克萨斯州医疗中心为名称合作研究中心（称为CRC）提供资金。 CRC的主要目标将通过一个基础科学家，生物医学工程师和一位在三个机构（BAYLOR医学院（BCM），赖斯大学，医学博士Anderson Anderson癌症中心）的跨学科，基础科学家，生物医学工程师和物理科学家的合作努力来实现。该CRC的总体目标是创建第一个在体育活动和模仿人类肠道许多方面的前体迷你模型系统。我们将使用源自人类肠活检的人类肠内肠动物（HIE）来解决有关由微生物引起的人类肠道疾病的关键问题，这些微生物引起了人类腹泻病，并导致全世界所有死亡的4％。非常需要充分反映相关的人类生理学，病理生理学和自然宿主病原体相互作用的新模型，因为大多数引起腹泻病的人类病原体都缺乏能够准确模仿人类疾病的动物模型。该CRC应用程序将一支具有多学科专业知识的团队整合，包括病毒学，细菌学的基础和转化研究以及创新，包括微生物组，基因组学，发育生物学和生理学，生物医学工程以及工程组织的生物材料开发，包括体外血管化和3D印刷，3D印刷，临床临床学和临床疾病学和临床疾病学。该CBC将由3个项目和3个核心设施组成。项目1将使用HIE分析遗传调节的宿主对人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来了解腹泻大肠杆菌感染的发病机理，包括表征急性感染和慢性感染之间差异的因素，组织的性质和病理机制。项目3将结合组织工程，生物材料设计和机制，以开发可用于机械刺激的HIE的量身定制的生物功能平台，这将促进细胞和组织极性以及完整的密码villus分化，从而获得带有共体和肠病毒的最爱感染。这三个相互关联和协同的项目将得到3个核心设施的专业和智力贡献的支持：行政核心，人类肠核以及基因组学和微生物组核心。将支持两个试点发展研究项目，其中一个由BCM资助。 CRC的成功取决于个人调查人员和中心领导者的完整专业知识，这些研究人员是高级科学家的管理者，他们在指导互动互动的多学科计划方面经历了经验丰富。生物医学工程师，本地生物学家和其他名称的研究人员之间的协作和迭代反馈将促进发展理想系统的进步，该系统将是最先进的，但对于农村使用感染性疾病实验室而言非常简单，并且可以在临床前研究中充分使用。