Molecular Mechanisms Governing Growth and Differentation within Intestinal Epithelia

The major focus of the laboratory is to unravel the molecular mechanisms that underlie the processes of growth and differentiation within intestinal epithelia. 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
3. pathological conditions such as cancer and inflammatory bowel disease.

We are particularly focused on identifying and characterizing the molecular mechanisms 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.

Selected Recent Publications

Malo MS, Zhang W, Abedrapo MA, Mozumder M, Pushpakaran P, Siddique A, Henderson JW, Hodin RA. Thyroid hormone positively regulates the enterocyte differentiation marker intestinal alkaline phosphates gene via an atypical response element. Molecular Endocrinology, 2004;18:1941-1962.

Alkhoury F, Malo MS, Mozumder M, Mostafa G, Hodin RA. Differential regulation of intestinal alkaline phosphatase gene expression by Cdx1 and Cdx2. Am J of Physiol. 2005;289:G285-290.

Archer SY, Johnson J, Kim H-J, Qing MA, Mou H, Vishnuvardhan D, Meng S, Hodin RA . The histone deacetylase inhibitor, butyrate downregulates cyclin B1 gene expression via a p21/waf1 dependent mechanism in human colon cancer cells. Am J Physiol. 2005;289:G696-703.

Malo MS, Pushpakaran P, Hodin RA.  A swinging cradle model for in vitro classification of different types of response elements of a nuclear receptor. Biochem and Biophys Res Comm 2005;18:490-497.

Malo MS, Mozumder M, Chen A, Mostafa G, Hodin RA.  pFRL7: an ideal vector for eukaryotic promoter analysis. Analytical Biochem. 2006;350:307-309.

Malo MS, Mozumder M, Zhang XB, Biswas S, Chen A, Bai LC, Merchant JL, Hodin RA.  Intestinal alkaline phosphatase gene expression is activated by ZBP-89. Am J Physiol  2006;290:G737-746.

Malo MS, Biswas S, Abedrapo M, Yeh L, Chen A, Hodin RA. The pro-inflammatory cytokines, IL-1beta and TNF-alpha, inhibit intestinal alkaline phosphatase gene expression. DNA and Cell Biology 2006;25:684-695.