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

项目总结/摘要 该提案包括一个为期三年的研究和职业发展计划，雷切尔尼克，医学博士，博士， 在免疫学和肠上皮生物学的交叉点实现独立的研究。博士 Niec在Sloan Kettering Institute和Internal Medicine Residency完成了免疫学博士培训 和威尔康奈尔医学院胃肠病学奖学金。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 教学法，赠款写作和实验室管理讲习班，获得技术技能和科学专门知识， 会议演示，并通过她的专门指导团队全面的指导计划。 博士Niec在细胞生物学方面有很强的背景，在洛克菲勒基金会的K 08奖项中， 大学，旨在扩大她在先进的显微镜，转录组学和干细胞（SC）生物学研究的技能 肠道SC（ISC）生态位的特征如何解释不同的线索，以指导健康和疾病中的SC活动。 炎症性肠病（IBD）是集中在肠上皮内的炎症性病症， 由遗传、环境和微生物因素驱动。肠上皮的维持依赖于ISC 而这又依赖于它们的局部信号的小生境来指导它们的活动。虽然许多利基因素源于 局部来源，肠上皮组织会发生全身性变化，表明血管特征可能 调节ISC活动。虽然炎症异常长期以来一直被认为是IBD的一个特征， 控制ISC行为的肠小生境的血管特征是未知的。核心假设是 血管系统是ISC功能的关键调节器，通过血管系统、ISC和其他小生境之间的直接信号传导， 细胞提出了两个具体目标：（1）确定毛细淋巴管对细胞网络的贡献 （2）确定淋巴源性Reln和淋巴干细胞对肠干细胞生态位的影响。 细胞相互作用对ISC维持和功能的影响。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学，以及 新的体外共培养和体内分子遗传学方法。这一建议的意义在于， 与上皮维持和再生的基本机制以及IBD的发病机制相关。 该提案在结合成像和转录组学的先进方法及其应用方面具有创新性。 应用于SC生态位生物学和肠道炎症。从长远来看，Niec博士的目标是运用专业知识， 获得了识别维持和调节肠道SC生态位的环境和炎症信号， 体内平衡和疾病，以改善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.