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

项目摘要 这个NIH ORIP K 01奖申请描述了一个5年的培训计划，旨在让我获得额外的 这样我就可以过渡到一个独立的R 01资助终身职位跟踪研究科学家。在 执行拟议的研究和职业发展计划，我将增加我的科学曲目，并获得 在肠道干细胞生物学、微生物组和微流控芯片器官技术方面的专业知识。使用这个新的 获得的专业知识，我将建立一个科学的利基，这将使我除了我的导师，并铺平道路， 一个强大的，由校外资助的研究项目在我的指导团队的支持下，我设计了一个 强大的研究计划，利用我在比较胃肠病学方面的广泛专业知识， 分子生物学具体而言，目标1将证明影响犬IBD的分子和遗传改变 在开发和验证了可以定量评估炎症反应的患者特异性IBD模型之后， 宿主-微生物组串扰的细胞和分子特征。目标2.将允许绘制微生物 响应于宿主微生物组细胞间串扰的特征和上皮完整性 水平的多组学（尤其是基因组学和转录组学）和RNA原位杂交。符合 ORIP的使命声明促进兽医科学家利用他们在比较医学方面的专业知识， 调查人类疾病，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内稳态的改变。 肠道疾病。此外，由于ORIP支持人类疾病的动物模型，我将使用狗作为一个 自发动物模型，以研究给予它们的肠上皮中的肠道微生物群的影响。 基因和生理上与人类相似该提案产生的结果直接影响到 对于人类疾病，因为它们将为遗传和转录组学改变提供新的见解， 维持肠道的慢性炎症这些发现可以应用于各种慢性疾病， 在流行病学上与微生物群系生态失调和肠道健康紊乱有关（即， 结直肠癌、糖尿病和阿尔茨海默病，仅举几例）。这些知识可以应用于 了解疾病的发展和新的治疗方法，旨在通过改变肠道内稳态， 肠中上皮-微生物组-免疫轴的扰动。总之，培训目标和职业生涯 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。

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.