Control of Intestinal Epithelial Function through Lymphatic-Intestinal Stem Cell Communication

项目摘要/摘要 这项提案包括一项为期三年的研究和职业发展计划，面向Rachel Niec，医学博士，博士到 在免疫学和肠道上皮生物学的交叉点上实现作为一名研究者的独立性。Dr。 NIEC在斯隆·凯特琳研究所完成了免疫学博士培训，并成为内科住院医师 和威尔康奈尔医学院的胃肠病研究员。研究和职业发展 活动将在洛克菲勒大学举行。Niec博士将从事职业发展活动，包括 教学、赠款撰写和实验室管理方面的讲习班、技术技能和科学专长的获得， 会议报告，以及通过她敬业的指导团队进行的全面指导计划。 Niec博士在细胞生物学方面有很强的背景，在洛克菲勒大学获得K08奖期间 大学，目标是扩大她在高级显微镜、转录学和干细胞(SC)生物学方面的技能以学习 肠道SC(ISC)生态位的特征如何解释不同的信号来指导SC在健康和疾病中的活动。 炎症性肠病(IBD)是集中在肠道上皮和肠道的炎症性疾病。 由遗传、环境和微生物因素驱动。肠上皮的维持依赖于ISC 这反过来又依赖于它们的利基来获得本地信号来指导它们的活动。虽然许多利基因素源于 局部来源，肠上皮组织会受到系统性变化的影响，这表明血管特征可能 规范ISC活动。虽然淋巴管异常一直被认为是IBD的一个特征，但 控制ISC行为的肠龛的血管特征尚不清楚。中心假设是 血管系统是ISC功能的关键调节器，通过血管系统、ISC和其他生态位之间的直接信号传递 细胞。提出了两个具体目标：(1)定义毛细淋巴管对细胞网络的贡献 包括肠道干细胞巢；(2)确定淋巴来源的Reln和淋巴：干细胞的影响 细胞相互作用对ISC维护和功能的影响。这些目标将通过组织清除和 先进的3D成像，已建立和新开发的单细胞和空间分辨率转录组，以及 新的体外共培养和体内分子遗传学方法。这项提议的意义在于它 与上皮维持和再生的基本机制及IBD的发病机制有关。 该提案在结合成像和转录学的先进方法以及他们的 在SC生态位生物学和肠道炎症方面的应用。从长远来看，Niec博士的目标是应用这些专业知识 获得识别维持和调节肠道SC生态位的环境和炎症信号 动态平衡与疾病，改善IBD的预防和治疗。

PROJECT SUMMARY/ABSTRACT This proposal comprises a three-year research and career development program for Rachel Niec, MD, PhD to achieve independence as an investigator at the intersection of immunology and intestinal epithelial biology. Dr. Niec completed her doctoral training in immunology at Sloan Kettering Institute and Internal Medicine Residency and Gastroenterology Fellowship at Weill Cornell Medical College. The research and career development activities will occur at Rockefeller University. Dr. Niec will engage in career development activities including didactics, workshops in grant writing and lab management, acquisition of technical skills and scientific expertise, conference presentations, and a comprehensive mentorship program through her dedicated mentoring team. Dr. Niec has a strong background in cell biology and, over the course of this K08 award at the Rockefeller University, aims to expand her skills in advanced microscopy, transcriptomics and stem cell (SC) biology to study how features of the intestinal SC (ISC) niche interpret diverse cues to direct SC activity in health and in disease. Inflammatory bowel diseases (IBD) are inflammatory conditions focused within the intestinal epithelium and driven by genetic, environmental, and microbial factors. Intestinal epithelial maintenance is dependent on ISC which in turn rely on their niche for local signals to direct their activity. While many niche factors emanate from local sources, intestinal epithelial tissues is subject to systemic changes suggesting vascular features may regulate ISC activity. While lymphatics abnormalities have long been appreciated as a feature of IBD, the vascular features of the intestinal niche that control ISC behavior are unknown. The central hypothesis is vasculature is a key regulator of ISC function, through direct signaling between vasculature, ISC and other niche cells. Two specific aims are proposed: (1) Define the contribution of lymphatic capillaries to the cellular network comprising the intestinal stem cell niche; (2) Determine the impact of lymphatic derived Reln and lymphatic:stem cell interactions on ISC maintenance and function. These aims will be addressed using tissue clearing and advanced 3D imaging, established and newly developed single cell and spatial resolution transcriptomics, and novel in vitro coculture and in vivo molecular genetic approaches. The significance of this proposal lies in its relevance to fundamental mechanism of epithelial maintenance and regeneration and to pathogenesis of IBD. The proposal is innovative in the combination of advanced methods in imaging and transcriptomics and their application to SC niche biology and intestinal inflammation. Long-term, Dr. Niec aims to apply the expertise gained to identify environmental and inflammatory signals that maintain and regulate the intestinal SC niche in homeostasis and disease to improve prevention and treatment of IBD.