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

通过淋巴-肠干细胞通讯控制肠上皮功能

• 批准号: 10924377
• 负责人: Rachel Niec
• 金额: $ 10.73万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10924377
• 关键词: Control; Intestinal; Epithelial; Function; through

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.

项目概要/摘要 该提案包括 Rachel Niec 医学博士、哲学博士的为期三年的研究和职业发展计划 作为免疫学和肠上皮生物学交叉领域的研究者获得独立。博士。 Niec 在斯隆凯特林研究所完成了免疫学博士培训并完成了内科住院医师培训 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进行。 Niec 博士将从事职业发展活动，包括 教学法、拨款写作和实验室管理研讨会、技术技能和科学专业知识的获取， 会议演讲，以及通过她专门的指导团队提供的全面指导计划。 Niec 博士在细胞生物学方面拥有深厚的背景，在洛克菲勒大学获得 K08 奖期间 大学旨在扩展她在先进显微镜、转录组学和干细胞 (SC) 生物学方面的技能以进行研究 肠道 SC (ISC) 生态位的特征如何解释不同的线索来指导健康和疾病中的 SC 活动。 炎症性肠病（IBD）是集中在肠上皮和肠道内的炎症性疾病。 受遗传、环境和微生物因素驱动。肠上皮的维持依赖于ISC 反过来，它们又依赖于本地信号的利基来指导其活动。虽然许多利基因素源自 局部来源，肠上皮组织会发生全身变化，表明血管特征可能 调节 ISC 活动。虽然淋巴管异常长期以来一直被认为是 IBD 的一个特征， 控制 ISC 行为的肠道生态位的血管特征尚不清楚。中心假设是 脉管系统是 ISC 功能的关键调节者，通过脉管系统、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 包括肠道干细胞生态位； (2)确定淋巴衍生Reln和淋巴:干的影响 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理和 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 新颖的体外共培养和体内分子遗传学方法。该提案的意义在于 与上皮维持和再生的基本机制以及 IBD 发病机制的相关性。 该提案的创新之处在于结合了成像和转录组学的先进方法及其各自的优势。 在 SC 生态位生物学和肠道炎症中的应用。从长远来看，Niec 博士的目标是应用专业知识 获得识别维持和调节肠道 SC 生态位的环境和炎症信号 体内平衡和疾病，以改善 IBD 的预防和治疗。