The Role of Wnt2b in Intestinal Health

Wnt2b 在肠道健康中的作用

• 批准号: 9888823
• 负责人: Amy E OConnell
• 金额: $ 16.95万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888823
• 关键词: Affect; Architecture; Biological Models; Biopsy; Biopsy Specimen; Boston; Cell Count; Cell Maintenance; Cells; Chronic; Clinical; Coculture Techniques; Death Rate; Development; Development Plans; Diarrhea; Digestive System Disorders; Disease; Doctor of Philosophy; Duodenum; Epithelial; Epithelial Cells; Epithelium; FOXL1 gene; Genetic Transcription; Goals; HIF1A gene; Health; Histologic; Human; Hypoxia; Hypoxia Inducible Factor; Immunofluorescence Immunologic; Immunologist; Immunology; In Situ Hybridization; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Instruction; Intestinal Diseases; Intestines; Investigation; Knockout Mice; Knowledge; LGR5 gene; Ligands; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Measures; Mentors; Mesenchymal; Mesenchyme; Messenger RNA; Modeling; Morbidity - disease rate; Morphology; Mucous Membrane; Mus; Neonatal; OLFM4 gene; Organogenesis; Organoids; Paper; Pathway interactions; Pediatric Hospitals; Physicians; Platelet-Derived Growth Factor alpha Receptor; Population; Process; Production; Radiation Injuries; Rare Diseases; Regulation; Reporting; Research; Research Personnel; Role; Scientist; Signal Transduction; Small Intestines; Source; Stromal Cells; System; Techniques; Training; WNT2B gene; Work; biological adaptation to stress; career; career development; fetal; genome editing; induced pluripotent stem cell; inflammatory disease of the intestine; integration site; interest; intestinal epithelium; intestinal homeostasis; knock-down; mRNA sequencing; mortality; neonatal period; neonate; response; small hairpin RNA; small molecule; stem cell biology; stem cell homeostasis; stem cells; transcriptomics

Project Summary Wnt signaling has been shown to be critical for intestinal health, and Wnts are required for intestinal stem cell (ISC) homeostasis. The roles of individuals Wnts in ISC regulation remain poorly defined. We have recently described a human congenital diarrheal disorder caused by deficiency of Wnt2b, marked by intestinal inflammation and loss of Lgr5+ISC, showing that Wnt2b is critical in the intestine. The goal of this proposed project is to clarify the need for Wnt2b in intestinal health. In Aim 1 we will investigate whether there is a developmental requirement for Wnt2b using mouse and human developmental models. In Aim 2 we will examine the impact of human Wnt2b on Lgr5+ISC homeostasis using a more mature enteroid model. We will also consider the mesenchymal versus epithelial sources of Wnt2b as components of Aims 1 and 2. This proposal is a five-year, mentored career development plan focused on expanding the investigator's knowledge of mucosal development and intestinal stem cell biology, as well as providing in depth instruction on genome editing and organogenesis techniques. The candidate is an MD/PhD trained physician scientist who is also an allergist/immunologist and neonatologist, and currently practices as a neonatologist at Boston Children's Hospital. The proposal will build on her strong immunology background by adding new expertise in stem cell biology and translational investigation through the tutelage of her co-mentors, Dr. Pankaj Agrawal and Dr. David Breault at the Manton Center for Orphan Disease Research and the Harvard Digestive Disease Center of Boston Children's Hospital. The proposed work will result in the candidate building niche expertise on regulators of intestinal development, upon which she plans to build her independent research career.

项目摘要 Wnt信号传导已被证明对肠道健康至关重要，并且Wnt是肠道健康所必需的。 肠干细胞（ISC）稳态。个体Wnt在ISC调节中的作用仍然很差 定义了我们最近描述了一种人类先天性牙周病， Wnt 2b，以肠道炎症和Lgr 5 +ISC丢失为标志，表明Wnt 2b在肠道炎症中至关重要。 肠子该项目的目标是阐明肠道健康对Wnt 2b的需求。在Aim中 1我们将研究是否有一个发展的需要，Wnt 2b使用小鼠和 人类发展模式。在目标2中，我们将研究人Wnt 2b对Lgr 5 +ISC的影响。 使用更成熟的类肠模型进行体内平衡。我们还将考虑间充质与 作为目的1和2的组分的Wnt 2b的上皮来源。 该提案是一项为期五年的、有指导的职业发展计划，重点是扩大 研究者对粘膜发育和肠干细胞生物学的了解，以及 提供关于基因组编辑和器官发生技术的深入指导。候选人是一名 医学博士/博士培训的医生科学家，也是过敏症专家/免疫学家和过敏症学家， 目前在波士顿儿童医院担任儿科医生。该提案将建立在她的基础上 通过增加干细胞生物学和翻译方面的新专业知识， 通过她的共同导师Pankaj Agrawal博士和大卫Breault博士的指导进行调查， 曼顿孤儿疾病研究中心和波士顿哈佛消化疾病中心 儿童医院拟议的工作将导致候选人建立利基专业知识， 肠道发育的调节剂，她计划建立她的独立研究生涯。