Deciphering the Role of Gut Microbiome in Inflammatory Bowel Disease Using a Canine Patient-Specific Gut-on-a-Chip

使用犬类患者特异性肠道芯片解读肠道微生物组在炎症性肠病中的作用

基本信息

批准号：
10192098
负责人：
Yoko Miyamoto Ambrosini
金额：
$ 10.26万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10192098
关键词：
16S ribosomal RNA sequencing Advanced Development Affect Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Attention Bioinformatics Canis familiaris Cell Culture Techniques Cells Chronic Coculture Techniques Colorectal Cancer Complex Development Development Plans Diabetes Mellitus Disease Disease model Electron Microscopy Enrollment Epidemiology Epithelial Experimental Models Extramural Activities Functional disorder Funding Gastroenterology Genetic Genetic Heterogeneity Genetic Variation Genome Genomics Germ-Free Goals Health Heterogeneity Homeostasis Human Image Immune Impairment In Situ In Situ Hybridization In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Knowledge Lead Learning Libraries Maps Medicine Mentored Research Scientist Development Award Mentors Microfabrication Microfluidic Microchips Microfluidics Mission Modeling Molecular Biology Molecular Genetics Molecular Profiling Mutation Names Organoids Outcome Pathogenesis Pathologic Patients Pharmaceutical Preparations Physiological Physiology Protocols documentation RNA RNA Sequences Research Research Personnel Role Scanning Scientist Techniques Technology Therapeutic Therapeutic Intervention Training Transmission Electron Microscopy United States National Institutes of Health Validation Visualization Work base career development cell type cohort combinatorial comparative design dysbiosis gut microbiome gut microbiota host microbiome human disease human model improved in vitro Model insight intestinal epithelium intestinal homeostasis microbial microbial signature microbiome microbiome research multiple omics new therapeutic target novel novel therapeutics organ on a chip patient oriented pre-clinical programs research and development response single-cell RNA sequencing skills spatiotemporal stem cell biology stem cells tenure track transcriptome transcriptomics translational medicine

项目摘要

PROJECT SUMMARY This NIH ORIP K01 award application describes a 5-year training plan designed to allow me to gain additional skill and knowledge so that I can transition to an independent R01-funded tenure track research scientist. In carrying out the proposed research and career development plan, I will add to my scientific repertoire and acquire expertise in intestinal stem cell biology, microbiome, and microfluidic organ-on-chip technology. Using this newly acquired expertise, I will establish a scientific niche that will set me apart from my mentors and pave the way to a robust, extramurally funded research program. With the support of my mentoring team, I have designed a robust research program that leverages my extensive expertise with comparative gastroenterology and molecular biology. Specifically, Aim 1 will demonstrate molecular and genetic alterations affecting canine IBD following the development and validation of a patient-specific IBD model that can quantitatively assess the cellular and molecular signature of host-microbiome crosstalk. Aim 2. will allow mapping of the microbial signature and epithelial integrity in response to the host-microbiome intercellular crosstalk by utilizing single-cell level multi-omics (especially genomics and transcriptomics) and RNA in situ hybridization. Consistent with the ORIP’s mission statements promoting veterinary scientists to employ their expertise in comparative medicine to investigate human diseases, my research will allow me to use my expertise in comparative gastroenterology as well as in primary stem cell culture to investigate alterations in intestinal homeostasis relevant to Inflammatory Bowel Disease. Also, as ORIP supports animal modeling of human diseases, I will be using the dog as a spontaneous animal model to investigate the effect of gut microbiota in the intestinal epithelium given their genetic and physiological similarity to humans. The results generated in this proposal have direct implications for human diseases, since they will provide new insights into genetic and transcriptomic alterations initiating or maintaining the chronic inflammation in the gut. Such findings can be applied to various chronic conditions that have been epidemiologically associated with microbiome dysbiosis and disturbances of intestinal health (i.e., Colorectal Cancer, Diabetes Mellitus, and Alzheimer’s Disease, to name a few). This knowledge may be applied to understand disease development and novel therapies aimed at modifying intestinal homeostasis via perturbation of epithelium-microbiome-immune axis in the intestine. In summary, the training goals and career development activities proposed in this application will promote my successful transition into independent research directions.

项目摘要该NIH Orip K01奖申请描述了一项为期5年的培训计划，旨在使我获得更多技能和知识，以便我可以过渡到由R01资助的独立终身研究科学家。在执行拟议的研究和职业发展计划，我将添加到我的科学曲目中并获得肠道干细胞生物学，微生物组和微流体器官片技术方面的专业知识。使用这个新获得的专业知识，我将建立一个科学的利基市场，这将使我与导师区分开来，并为一个健壮的外部资助研究计划。在我的心理团队的支持下，我设计了强大的研究计划，利用我的广泛专业知识，以比较胃肠病学和分子生物学。具体而言，AIM 1将证明影响犬IBD的分子和遗传改变遵循特定于患者的IBD模型的开发和验证，该模型可以定量评估宿主 - 微生物组串扰的细胞和分子特征。 AIM 2。将允许微生物映射通过使用单细胞的签名和上皮完整性响应宿主 - 微生物组间串扰水平的多媒体（尤其是基因组学和转录组学）和RNA原位杂交。与 Orip的任务陈述促进兽医科学家在比较医学方面使用其专业知识调查人类疾病，我的研究将使我能够在比较胃肠病学方面使用我的专业知识作为以及原发性干细胞培养以研究与炎症有关的肠内稳态变化排便。另外，由于Orip支持人类疾病的动物建模，我将使用狗作为赞成动物模型以研究肠道微生物群在肠上皮的作用与人类的遗传和身体相似。本提案中产生的结果具有直接影响对于人类疾病，由于它们将提供有关遗传和转录组改变的新见解，或保持肠道中的慢性炎症。这样的发现可以应用于各种慢性条件在流行病学上与微生物组营养不良和肠道健康灾难相关（即大肠癌，糖尿病和阿尔茨海默氏病，仅举几例）。可以应用这些知识了解疾病发育和新型疗法，旨在通过肠中上皮 - 微生物 - 免疫轴的扰动。总而言之，培训目标和职业本申请中提出的开发活动将促进我的成功过渡到独立的过渡研究方向。