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：
10369046
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369046
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 Persons 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 canine model 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.

项目概要此 NIH ORIP K01 奖励申请描述了一项为期 5 年的培训计划，旨在让我获得额外的知识技能和知识使我可以过渡到 R01 资助的独立终身教授研究科学家。执行拟议的研究和职业发展计划，我将增加我的科学技能并获得肠道干细胞生物学、微生物组和微流控芯片器官技术方面的专业知识。获得专业知识后，我将建立一个科学领域，使我与我的导师区分开来，并为我的未来铺平道路。在我的指导团队的支持下，我设计了一个强大的、外部资助的研究项目。强大的研究计划利用了我在广泛的胃肠病学和比较胃肠病学方面的专业知识具体来说，目标 1 将展示影响犬 IBD 的分子和遗传改变。在开发和验证患者特异性 IBD 模型后，该模型可以定量评估目标 2. 宿主-微生物组串扰的细胞和分子特征将有助于绘制微生物图谱。利用单细胞响应宿主微生物组细胞间串扰的特征和上皮完整性水平多组学（尤其是基因组学和转录组学）和RNA原位杂交一致。 ORIP 的使命宣言促进兽医科学家利用他们在比较医学方面的专业知识研究人类疾病，我的研究将使我能够利用我在比较胃肠病学方面的专业知识以及在原代干细胞培养中研究与炎症相关的肠道稳态的变化此外，由于 ORIP 支持人类疾病的动物模型，我将使用狗作为模型。自发动物模型研究肠道微生物群对肠上皮的影响该提案产生的结果具有直接影响。对于人类疾病，因为它们将为遗传和转录组改变的启动或改变提供新的见解这些发现可以应用于多种慢性疾病。流行病学上与微生物群失调和肠道健康紊乱有关（即例如，结直肠癌、糖尿病和阿尔茨海默病等）这些知识都可以应用。了解疾病的发展和旨在改变肠道稳态的新疗法肠道上皮-微生物-免疫轴的扰动总之，训练目标和职业。本申请中提出的发展活动将促进我成功过渡到独立研究方向。