Organogenesis and tissue homeostasis within the gastrointestinal (GI) tract require continuous crosstalk between the endodermal epithelium and adjacent mesenchyme. Much of what is known about GI development has been learned from studies of the endoderm and its derivatives; however, little is known about the genetic and cellular mechanisms governing gut mesenchymal development. This grant application is designed to uncover the mechanisms that underlie this important, yet poorly understood developmental system. The proposed studies are centered on charactering on the molecular basis of growth and patterning in the gut mesenchyme. We will use a combination of mouse genetics and cellular approaches to address three principle questions. First, we will define a Sox-dependent molecular switch that is responsible for coordinating early primitive progenitor expansion and subsequent mesenchymal differentiation. In the second part of the grant, we will identify the signaling pathways that act in concert to control smooth muscle growth and intestinal organ size. In the third part of the grant, we will explore a novel mesenchymal mechanism that is involved in suppression of intestinal polyposis. We believe that completion of the proposed studies will significantly further our understanding of the fundamental mechanisms controlling gut development and homeostasis. This knowledge gained from our studies will ultimately contribute to the development of new therapies for treating GI-related diseases and cancers.

Public Health Relevance

This grant proposal is designed to uncover the mechanism mediating the mesenchymal- epithelial crosstalk in the gastrointestinal tract. The proposed studies are focused on the molecular and signaling controls of growth and patterning in the gut mesenchyme during embryonic development and postnatal homeostasis. We believe that completion of the proposed studies will significantly further our understanding of the molecular basis of gut development. This knowledge will not only offer novel insight into the mechanisms that govern GI organogenesis and homeostasis, but could also ultimately contribute to the development of new therapeutic strategies for treating GI-related diseases and cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099510-05
Application #
9457417
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Greenwel, Patricia
Project Start
2014-04-15
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
Rajurkar, Mihir; Dang, Kyvan; Fernandez-Barrena, Maite G et al. (2017) IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis. Cancer Res 77:320-329
Cotton, Jennifer L; Li, Qi; Ma, Lifang et al. (2017) YAP/TAZ and Hedgehog Coordinate Growth and Patterning in Gastrointestinal Mesenchyme. Dev Cell 43:35-47.e4
Liu, Xiangfan; Li, Huapeng; Rajurkar, Mihir et al. (2016) Tead and AP1 Coordinate Transcription and Motility. Cell Rep 14:1169-1180