EXCEED THE SPACE PROVIDED. Thyroid Hormone (T3) is one of the most potent regulators of intestinalepithelialstructure and function. T3 appears to play a vital role in virtually all aspects of gut epithelial biology, including normal development, maintenance of tissue homeostasis in the adult, as well as the process of neoplasia. The overall goals of this work are to unravel the molecular mechanisms by which T3 exerts its profound effects on gut epithelialdifferentiation. The initial model of T3 action involved its binding to a receptor protein (TR) which then interacted with target genes at sites called thyroid response elements (TRE), resulting in either positive or negative changes in transcriptional rates. Over the past several years, however, a paradigm shift has occurred such that T3 action is now known to involve a variety of other proteins (co-activators and co-repressors). Furthermore, the T3-TR interaction with DNA is highly regulated by the chromatin structure (histones). This research proposal is designed to elucidate the complex molecular interactions that underlie the T3-mediated effects on intestinal epithelia. In previous work, thyroid hormone has been shown to differentially regulate gut gene transcription, increasing intestinal alkalinephosphatase (IAP) and decreasing lactase expression.
In Specific Aim #1, the mechanism by which T3 alters these two target genes will be examined by using two novel approaches, stable reporter assays and the chromatin immuno-precipitation (ChIP) assay. These two approaches have been chosen specifically because they provide information regarding transcriptional events in the context of endogenous chromatin, rather than the naked DNA used in past molecular studies.
In Specific Aim #2, the stable reporter assays will be further utilized in order to elucidate the role that histone modification plays in T3-mediated transcriptionalevents within the gut. We will examine agents that induce histone hyperacetylation (short chain fatty acids), as well as a family of enzymes that deacetylate histones (HDAC 1, 2, and 3). Finally, in Specific Aim #3, two potential endogenous inhibitors of T3 action within the gut will be studied. The cyclin Dl (CD1) inhibition of T3 action may underlie its fundamental 'anti-differentiating' effects, as well as being related to its role in colon carcinogenesis. The T3 inhibitory effects of the non-receptor, TRoc-2, may underliethe gut mucosal dysfunction that occurs in a variety of disease states, including prolonged starvation and severe trauma. It is hoped that an elucidation of the molecular events that govern T3 action within the gut will provide potential therapeutic targets that could be manipulated to maintain the integrity of the intestinalmucosa under pathologic conditions. PERFORMANCE SITE ========================================Section End===========================================
| Malo, Madhu S; Moaven, Omeed; Muhammad, Nur et al. (2014) Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates. Am J Physiol Gastrointest Liver Physiol 306:G826-38 |
| Alam, Sayeda Nasrin; Yammine, Halim; Moaven, Omeed et al. (2014) Intestinal alkaline phosphatase prevents antibiotic-induced susceptibility to enteric pathogens. Ann Surg 259:715-22 |
| Moss, Angela K; Hamarneh, Sulaiman R; Mohamed, Mussa M Rafat et al. (2013) Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate. Am J Physiol Gastrointest Liver Physiol 304:G597-604 |
| Kaliannan, Kanakaraju; Hamarneh, Sulaiman R; Economopoulos, Konstantinos P et al. (2013) Intestinal alkaline phosphatase prevents metabolic syndrome in mice. Proc Natl Acad Sci U S A 110:7003-8 |
| Nucera, Carmelo; Nehs, Matthew A; Nagarkatti, Sushruta S et al. (2011) Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer. Oncologist 16:296-309 |
| Ramasamy, Sundaram; Nguyen, Deanna D; Eston, Michelle A et al. (2011) Intestinal alkaline phosphatase has beneficial effects in mouse models of chronic colitis. Inflamm Bowel Dis 17:532-42 |
| Chen, Kathryn T; Malo, Madhu S; Beasley-Topliffe, Laura Kline et al. (2011) A role for intestinal alkaline phosphatase in the maintenance of local gut immunity. Dig Dis Sci 56:1020-7 |
| Ebrahimi, Farzad; Malo, Madhu S; Alam, Sayeda Nasrin et al. (2011) Local peritoneal irrigation with intestinal alkaline phosphatase is protective against peritonitis in mice. J Gastrointest Surg 15:860-9 |
| Chen, Kathryn T; Malo, Madhu S; Moss, Angela K et al. (2010) Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase. Am J Physiol Gastrointest Liver Physiol 299:G467-75 |
| Malo, M S; Alam, S Nasrin; Mostafa, G et al. (2010) Intestinal alkaline phosphatase preserves the normal homeostasis of gut microbiota. Gut 59:1476-84 |
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