This project is focused on evaluating the role fibroblast growth factors (FGFs) play in promoting intestinal stem cell (ISC) expansion following chemotherapy-induced intestinal damage.
The aims outlined in the proposal will: 1. evaluate the expression patterns of several FGF-10 and its corresponding receptors (FGFR1 and R2) in the intestinal mucosa following damage, 2. develop intestinal epithelium-specific knockouts of the receptors to evaluate their roles in ISC expansion following damage, and 3. develop intestinal epithelium-specific knock-in mice that allow me to chronically activate either of the receptors to study how chronic activation influences the intestinal epithelium. By completing these aims I will receive extensive training in generating and using transgenic animal models and will learn the intricacies of growth factor signaling in the intestine. Both areas are critical to developing my own independent research program. My immediate career goal is understanding how factors, such as FGFs, can effect ISC expansion. Transgenic animal models are becoming a key tool in basic bio medical research. Therefore, developing the models outlined in my proposal is a critical part of my studies. As part of my career development plan, I have assembled an advisory committee composed of senior investigators with expertise in generating transgenic animal models, growth factor signaling and stem cell regulation. Their role is help me develop the understanding of these areas which, in turn, will allow me to build my own research program. In the long term, I anticipate my interest will expand from FGFs to additional factors there are clearly numerous factors simultaneously influencing the ISC. My ultimate goal is to develop such an understanding of how to control ISC expansion that clinical applications, for example, manipulating ISCs in situ by drug delivery or ex vivo culturing of autologous ISCs, would be developed. My current research environment is ideal for progressing to such a stage, from technical resources to equipment to experienced Gl researchers. In addition, being part of a clinical division in a clinical department, but surrounded by basic scientists places me in an advantageous position of developing a research program that promotes bench-to-bedside science.
Much like the skin, the cells lining the intestinal tract are constantly being replenished. This is accomplished by intestinal stem cells which are tightly controlled to provide the appropriate rate of adding new cells. The factors that control intestinal stem cells are not completely understood. In times of damage, such as after chemotherapy, or in cancer, where stem cells are uncontrolled, understanding how to control stem cells may provide clinical interventions to promote repair or reduce cancer formation
|King, Stephanie L; Dekaney, Christopher M (2013) Small intestinal stem cells. Curr Opin Gastroenterol 29:140-5|
|King, Stephanie L; Mohiuddin, Jahan J; Dekaney, Christopher M (2013) Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage. Am J Physiol Gastrointest Liver Physiol 305:G151-62|
|Garrison, Aaron P; Helmrath, Michael A; Dekaney, Christopher M (2009) Intestinal stem cells. J Pediatr Gastroenterol Nutr 49:2-7|