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.

 U19 整体申请说明（由申请人提供）：本申请要求为德克萨斯医学中心的 NAMSED 合作研究中心（简称 CRC）提供资金。该 CRC 的主要目标将通过来自三个机构（贝勒医学院 (BCM)、莱斯大学、MD 安德森癌症中心）的基础科学家、生物医学工程师和医师科学家组成的多学科综合团队的共同努力来实现。该 CRC 的总体目标是创建第一个离体迷你肠道模型系统，该系统具有生理活性并模仿人类肠道的许多方面。我们将使用从人类肠道活检中提取的人类肠道肠类 (HIE) 来解决有关人类肠道疾病的关键问题，这些疾病是由微生物引起的，这些微生物会导致人类腹泻病，并导致全球死亡人数约 4%。由于大多数引起腹泻病的人类病原体缺乏准确模拟人类疾病的动物模型，因此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。该CRC应用程序整合了一支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 将由 3 个项目和 3 个核心设施组成。项目 1 将使用 HIE 来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差异的因素、组织向性和病理学机制。项目3将结合组织工程、生物材料设计和机械生物学，为HIE开发定制的生物功能平台，该平台可以受到机械刺激，并促进细胞和组织极性以及完整的隐窝-绒毛分化，以促进共生菌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 个核心设施的专业和智力贡献的支持：管理核心、人肠类核心以及基因组学和微生物组核心。两项试点发展研究项目将得到支持，其中一项由 BCM 资助。该 CRC 的成功取决于个别研究者和中心领导的专业知识的互补，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兼管理人员。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开发理想系统的进展，该系统将是最先进的，但足够简单，适合传染病实验室的常规使用，并且足够稳健，适合用于临床前研究。