The epithelial lining of the intestine has the remarkable ability to maintain consistent cell-type composition over the course of a lifetime despite constant renewal. Many micro-environmental signals and morphogens important for maintaining epithelial cell-type composition have been identified. However, a major gap in our knowledge is how intestinal epithelial cells make sense of a multitude of environmental signals to produce consistent cellular decisions required for tissue homeostasis. The proposed research focuses on how TGF-?, a micro-environmental signal essential for intestinal development and health, is integrated into cell differentiation decisions in the intestinal epithelium. Specific focuses include:
(Aim 1) identifying the signaling effectors and transcriptional regulators that confer TGF-??s effects on cell differentiation, (Aim 2) determining which cell- types transduce the epithelial response to TGF-? in vitro and in vivo and (Aim 3) discerning how signaling downstream of TGF-? and Wnt3a stimulation converge to regulate the production of enteroendocrine cells, an epithelial cell-type that is essential for digestion and nutrient uptake. To achieve these Aims and to accomplish my postdoctoral training objectives, I will work closely with my co-sponsors Dr. Steven Altschuler and Dr. Ophir Klein. These studies will be significantly facilitated by the Altschuler lab?s novel enteroid monolayer culture system and accompanying analytical methods and the Klein lab?s expertise in stem cell niche biology and perturbing morphogen signaling in vivo. Furthermore, these studies will benefit from excellent collaborators at UCSF with expertise in genomics, gastrointestinal biology, TGF-? signaling biology, and murine experimental biology. Finally, because dysregulation of intestinal epithelial cell differentiation and impaired TGF-? signaling occur in many gastrointestinal disorders including developmental disorders, inflammatory bowel disease, my aim is that my research will contribute significantly to our understanding of and ability to treat such diseases.
A central question in the study of renewing tissues is how a multitude of signals and pathways work together to control cell proliferation, differentiation, and death. The proposed research focuses on dissecting how TGF-?, a growth factor that is critical for gut development and function, shapes cell differentiation in the constantly renewing gut epithelium. The proposed research is essential for understanding and treating gastrointestinal disorders, such as cancer and inflammatory bowel disease, which stem from loss of epithelial homeostasis and impaired TGF-? signaling.
