Transcriptional Regulation of NHE-3 Isoform in Human Intestine

University Of Illinois At Chicago, Chicago IL

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Abstract

The molecular mechanisms involved in the regulation of the human intestinal NaCI absorption,[unreadable] mediated by the concerted action of dual ion exchanges of Na/H+ and Cl-/HCO3- are not well understood.[unreadable] Our prior studies of the human small intestine and colon suggest that the Na+/H+ exchanger, NHE3, may be[unreadable] the predominant isoform involved in Na+ absorption in the small intestine, whereas NHE2 is important[unreadable] for colonic Na+ absorption. It is, therefore, crucial to investigate the regulation of human Na+/H+ exchangers[unreadable] for a better understanding of normal human intestinal physiology and to understand the molecular basis of[unreadable] diarrheal disorders. Our studies of the NHE3 promoter showed that NHE3 expression is regulated by a[unreadable] number of transcription factors including AP-2, Egr-1 and Sp1 family members. The regulation of NHE3[unreadable] exchanger activity by different stimuli such as serotonin, nitric oxide, IFN-y, PMA and EPEC infection was also[unreadable] demonstrated. We hypothesize that cis-elements in the NHE3 promoter region and their cognate[unreadable] transcription factors mediate the processes involved in NHE3 regulation during basal transcription,[unreadable] tissue-specific expression and intestinal inflammation and propose the following three specific aims[unreadable] to address them.[unreadable] Specific Aim 1 will elucidate the role of inflammatory mediators in transcriptional regulation of NHE3 by[unreadable] investigating the mechanisms involved in the regulation of the NHE3 gene expression by EPEC infection and[unreadable] associated inflammatory mediators such as TNFalpha and IFN-y and by characterizing the cis-regulatory elements[unreadable] and their corresponding trans-acting factors that mediate the effects of these agents. Our Specific Aim 1 will[unreadable] interact with Project 1 and Project 4.[unreadable] Specific Aim 2 is designed to determine the molecular mechanisms involved in the transcriptional[unreadable] regulation of the NHE3 gene in response to mitogenic stimulus PMA, through characterization of the putative[unreadable] PMA- response elements and transcription factors Egr-1, Sp1 and Sp3.[unreadable] Specific Aim 3 will identify the cis- and trans-acting factors that regulate cell-specific expression of the[unreadable] NHE3 gene through epigenomic mechanisms utilizing, C2/bbe, Caco-2, NCM460, LnCap, PCS, HepG-2,[unreadable] MDCK cells as well as NIH3T3 mouse fibroblast cell line.[unreadable]