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: 10591264
• 负责人: Rachel Niec
• 金额: $ 7万
• 依托单位: ROCKEFELLER UNIVERSITY
• 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 2023-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591264
• 关键词: 3-Dimensional; Address; Affect; Award; Biology; Blood Vessels; Cardiac Myocytes; Cell Communication; Cell Maintenance; Cell physiology; Cells; Cellular biology; Chronic; Coculture Techniques; Communication; Complex; Crohn' s disease; Cues; Data; Dedications; Development; Disease; Doctor of Philosophy; EGF gene; Educational workshop; Epithelial Cells; Epithelium; Extracellular Matrix; Fellowship; Fibrosis; Gastroenterology; Gene Expression; Genetic; Grant; Hair; Hair follicle structure; Health; Homeostasis; Image; Immune; Immunofluorescence Immunologic; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Institute of Medicine (U.S.); Internal Medicine; Intestines; Knowledge; Laboratories; Large Intestine; Life; Ligands; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Maintenance; Malignant Neoplasms; Maps; Mentors; Mentorship; Mesenchymal; Methods; Microscopy; Mission; Molecular Genetics; Morbidity - disease rate; Natural regeneration; Neurons; Organoids; Paneth Cells; Pathogenesis; Predisposition; Prevention; Process; Program Development; Regulation; Research Personnel; Residencies; Resolution; Role; Signal Transduction; Skin; Small Intestines; Structure; Surface; System; Technical Expertise; Testing; Three-Dimensional Imaging; Tissues; Training; Ulcerative Colitis; United States National Institutes of Health; Universities; WNT3 gene; Writing; antagonist; base; career development; cell behavior; cell type; defined contribution; epithelial stem cell; gain of function; gastrointestinal; genetic approach; gut inflammation; improved; in vivo; inhibitor; innovation; intestinal epithelium; loss of function; lymphatic drainage; lymphatic malformations; lymphatic vasculature; medical schools; microbial; migration; mouse model; notch protein; novel; novel therapeutic intervention; nutrient absorption; premature; prevent; programs; receptor; regenerative; research and development; self-renewal; single-cell RNA sequencing; skills; source localization; spatial integration; stem cell biology; stem cell function; stem cell niche; stem cells; symposium; therapeutic target; transcriptomics

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.

项目摘要/摘要 该建议包括为Rachel Niec，MD，PhD的三年研究和职业发展计划 在免疫学和肠上皮生物学的交集中成为研究者的独立性。博士 NIEC在斯隆·凯特林研究所（Sloan Kettering Institute）和内科住院医师（Sloan Kettering Institute）完成了她的免疫学博士培训 威尔·康奈尔医学院（Weill Cornell Medical College）和胃肠病学奖学金。研究和职业发展 洛克菲勒大学将举行活动。 NIEC博士将从事职业发展活动，包括 教学，赠款写作和实验室管理的讲习班，获取技术技能和科学专业知识， 会议演讲，以及通过其专门的指导团队的全面指导计划。 Niec博士在细胞生物学方面具有很强的背景，在洛克菲勒（Rockefeller）的K08奖中 大学旨在扩大她在高级显微镜，转录组学和干细胞（SC）生物学方面的技能 肠道SC（ISC）利基市场的特征如何将各种线索解释为直接在健康和疾病中进行SC活动。 炎症性肠病（IBD）是集中在肠上皮内的炎症疾病， 受遗传，环境和微生物因素驱动。肠上皮维护取决于ISC 反过来，这依靠他们的利基市场来指导其活动。而许多利基因素源自 局部来源，肠上皮组织受到全身变化，表明血管特征可能 调节ISC活性。虽然淋巴异常长期以来一直是IBD的特征，但 控制ISC行为的肠道壁基的血管特征尚不清楚。中心假设是 脉管系统是ISC功能的关键调节剂，通过脉管系统，ISC和其他小众之间的直接信号传导 细胞。提出了两个具体目标：（1）定义淋巴毛细血管对细胞网络的贡献 包括肠道干细胞生态位； （2）确定淋巴衍生的复发和淋巴的影响：茎 ISC维护和功能上的细胞相互作用。这些目标将使用组织清除和 先进的3D成像，建立和新开发的单细胞和空间分辨率转录组学，以及 新型体外共培养和体内分子遗传学方法。该提议的重要性在于 与上皮维持和再生以及IBD发病机理的基本机制有关。 该提案在成像和转录组学中的高级方法及其中具有创新性 应用于SC生物学和肠道炎症。长期，NIEC博士旨在应用专业知识 获得以确定维护和调节肠道SC生态位的环境和炎症信号 稳态和疾病，以改善IBD的预防和治疗。