The Role of Wnt2b in Intestinal Health

Wnt2b 在肠道健康中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 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的。我们最近描述了一种由缺乏 Wnt2b，以肠道炎症和 Lgr5+ISC 丢失为标志，表明 Wnt2b 在肠。该拟议项目的目标是阐明 Wnt2b 在肠道健康中的需求。瞄准 1 我们将使用鼠标调查 Wnt2b 是否存在发育要求人类发展模型。在目标 2 中，我们将研究人类 Wnt2b 对 Lgr5+ISC 的影响使用更成熟的肠样模型进行稳态。我们还将考虑间充质与 Wnt2b 的上皮来源作为目标 1 和 2 的组成部分。该提案是一个为期五年的、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道干细胞生物学的了解，以及提供有关基因组编辑和器官发生技术的深入指导。候选人是一位受过医学博士/博士学位训练的医师科学家，同时也是过敏症专家/免疫学家和新生儿学家，以及目前在波士顿儿童医院担任新生儿科医生。该提案将以她为基础通过增加干细胞生物学和转化方面的新专业知识，拥有强大的免疫学背景在她的共同导师 Pankaj Agrawal 博士和 David Breault 博士的指导下进行了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在以下方面建立利基专业知识肠道发育的调节因子，她计划在此基础上建立自己的独立研究生涯。