I have long aspired to work in the field of academic surgery, combining both clinical and scientific research activities. My research interest lies in the area of cell cycle physiology as it relates to intestinal epithelial cell growth and differentiation. I have devoted two years to the acquisition of knowledge and technical skills in this area of molecular biology, but further experience is needed in advanced molecular biology techniques and theory which will allow me to fulfill my goal of becoming an independent researcher. The proposed project, therefore, will serve both as a means of pursuing investigations in my field of interest, as well as learning new and important concepts and techniques. In the proposed studies, I will examine the molecular mechanisms governing the activation of the human p21 gene during the process of intestinal epithelial differentiation, using an in vitro model of enterocyte differentiation, sodium butyrate (NaBu)-treated HT-29 cells. I plan to identify the DNA cis-element and the activating transcription factor which interact under these conditions to result in induction of the gene. Since NaBu is known to induce histone hyperacetylation, I will also examine the link between histone hyperacetylation and p21 transactivation. This is an exciting area of rapidly advancing knowledge. These studies should enhance our knowledge of the fundamental aspects of p21 regulation during intestinal epithelial differentiation, and as such, will impact on our general understanding of normal and deregulated cell growth. The rich environment afforded me at Beth Israel Hospital and Harvard Medical School, will not only allow me to continue my clinical practice in general surgery, but will provide the necessary tools to achieve my research goals a well. Such an environment will allow me to pursue knowledge in all aspects of my research activities. The enlistment of experienced consultants in the field, as well as access to a plethora of scientists in the area is also a certain advantage in this pursuit. This award will provide the financial means for making these goals possible, and is therefore critical for the realization of my scientific career plans.
|Archer, Sonia Y; Johnson, Jennifer; Kim, Hyun-Ju et al. (2005) The histone deacetylase inhibitor butyrate downregulates cyclin B1 gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells. Am J Physiol Gastrointest Liver Physiol 289:G696-703|
|Hinnebusch, Brian F; Ma, Qing; Henderson, J Welles et al. (2002) Enterocyte response to ischemia is dependent on differentiation state. J Gastrointest Surg 6:403-9|
|Hinnebusch, Brian F; Meng, Shufen; Wu, James T et al. (2002) The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J Nutr 132:1012-7|
|Wu, J T; Archer, S Y; Hinnebusch, B et al. (2001) Transient vs. prolonged histone hyperacetylation: effects on colon cancer cell growth, differentiation, and apoptosis. Am J Physiol Gastrointest Liver Physiol 280:G482-90|
|Archer, S Y; Johnson, J J; Kim, H J et al. (2001) p21 gene regulation during enterocyte differentiation. J Surg Res 98:4-8|
|Archer, S; Meng, S; Wu, J et al. (1998) Butyrate inhibits colon carcinoma cell growth through two distinct pathways. Surgery 124:248-53|