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.
Human Wnt2b deficiency is marked by neonatal onset diarrhea and intestinal inflammation and features diminished Lgr5+ intestinal stem cells (ISC), which function to maintain the intestinal epithelium. Given that Wnt2b was not previously thought to be required for intestinal health, this project seeks to understand how loss of Wnt2b leads to loss of Lgr5+ISC and to development of intestinal disease. The results of this investigation may have wide implications, as ISC health is linked to a number of other, more common, intestinal disorders such as inflammatory bowel disease and gastrointestinal cancers.
