Research Type:

Minimally Invasive Surgery
Pancreatic
Gastrointestinal Epithelial Biology
Clinical Effectiveness
Clinical Research

Laboratory of Gastrointestinal Epithelial Biology

Principal Investigator:
Richard A. Hodin, M.D.

Group members:

Madhu S. Malo, MBBS, PhD
Golam Mostafa, MD
Sayeda Nasrin Alam, MD
Kathryn Chen, MD
Sundaram Ramasamy, PhD

The major focus of the laboratory is to unravel the molecular mechanisms that underlie the processes of growth and differentiation within intestinal epithelia. The small intestine is lined by a simple columnar epithelium in which pluripotent, proliferating crypt cells (stem cells) give rise to four distinct lineages of differentiated cells, including enterocytes (95%), goblet, and enteroendocrine cells on the villi, and paneth cells at the crypt base. The various projects ongoing in the lab relate to understanding the differentiation process in the contexts of (1) normal development, (2) homeostasis within the adult, and (3) pathological conditions such as starvation, cancer, and inflammatory bowel disease.

(1) 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.

(2) 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 which 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.

(3) 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 and inflammation. We have identified a specific alteration in the phenotype of the enterocyte (IAP gene silencing) that appears to be a reliable marker for this gut mucosal failure. Recent work from the lab suggests that this loss of IAP expression may be a key factor in the breakdown of gut mucosal defense that is seen in starvation and other diseases.

We are employing IAP knockout and IAP transgenic mice in order to examine the role of this protein in regard to the gut barrier, and to lay the groundwork for IAP-based therapies that could be used clinically to help patients in the settings of severe trauma, sepsis, and critical illness. 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. We have been particularly interested in the beneficial effects of fiber-derived short-chain fatty acids in blocking the development and growth of colon tumors.