Richard A. Hodin, MD
Molecular Mechanisms Governing Growth and Differentation within Intestinal Epithelia
The various projects ongoing in the lab relate to understanding the differentiation process in the contexts of:
- normal development
- homeostasis within the adult
- pathological conditions such as cancer and inflammatory bowel disease
We are particularly focused on identifying and characterizing transcription factors that govern the normal crypt-villus differentiation program, as well as determining those factors that go awry in a variety of human disease states involving the gut.
Some of our current projects include:
- Gut Development
The mammalian small intestine undergoes a very precise and complex series of morphological and biochemical changes during pre- and post-natal development. Among the most critical factors involved in this process is thyroid hormone. Animals that are hypo-thyroid or lack thyroid hormone receptors exhibit profound abnormalities within the gut mucosa. We are investigating the molecular mechanisms by which thyroid hormone exerts its effects upon intestinal epithelial growth and differentiation.
- Gut Homeostasis
The gut epithelium is a dynamic structure that undergoes a continuous cycle of self-renewal, with pluripotent stem cells located in the crypts giving rise to fully-differentiated villus cells. We are studying the differentiation process of the enterocyte, the cell that comprises 95% of all villus cells and is responsible for the nutrient digestion and absorption that is critical to life. The enterocyte marker gene, intestinal alkaline phosphatase (IAP) is being used as a tool to identify and characterize transcription factors that mediate the differentiation process. Among the mechanisms that underlie gut differentiation is a specific alteration in chromatin structure. We have therefore employed novel techniques to examine the role that histone proteins play in enterocyte growth and differentiation.
- Gut Pathology
Unfortunately, the normal differentiation process goes awry under a variety of conditions, many of which are seen in surgical patients. Perhaps most notable is the gut mucosal failure that occurs with starvation, ischemia or inflammatory conditions. We have identified specific alterations in the phenotype of the enterocyte that appears to be a reliable marker for this gut mucosal failure and have ongoing studies that are geared toward an elucidation of this abnormal phentoype and the molecular events that cause it. In addition, it is quite clear that cancer of the GI tract (i.e., colon cancer) represents a failure in the normal growth and differentiation cues within the epithelium. We are using a variety of human colon cancer-derived cell lines as well as in vivo models of colon carcinogenesis to unravel the transcriptional events that govern the neoplastic process.