Administrative Supplement: The Role of Wnt2b in Small Intestinal Health

项目摘要 WNT信号已被证明对肠道健康至关重要，而WNT是必需的 肠道干细胞(ISC)动态平衡。个体WNT在ISC监管中的作用仍然很差 已定义。我们最近描述了一种人类先天性腹泻疾病，原因是缺乏 Wnt2b，以肠道炎症和Lgr5 ISC丢失为标志，表明Wnt2b在 肠子。这一拟议项目的目标是阐明Wnt2b在肠道健康方面的需求。在AIM 1我们将调查Wnt2b是否有发育需要，使用小鼠和 人类发育模型。在目标2中，我们将研究人类Wnt2b对Lgr5 ISC的影响 使用更成熟的肠样体模型的动态平衡。我们还将考虑间充质与 Wnt2b作为AIMS 1和2的组成部分的上皮来源。 这项建议是一项为期五年、有指导的职业发展计划，重点是扩大 研究人员对粘膜发育和肠道干细胞生物学的知识，以及 提供关于基因组编辑和器官发生技术的深入指导。候选人是一位 受过医学博士培训的内科科学家，也是过敏症专家/免疫学家和新生儿专家，以及 目前在波士顿儿童医院担任新生儿科医生。这项提议将以她为基础 通过增加干细胞生物学和翻译方面的新专业知识，增强免疫学背景 通过她的联合导师Pankaj Agrawal博士和David 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在以下方面建立适当的专业知识 肠道发育调节者，她计划在此基础上建立她的独立研究生涯。

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.