Abstract

The goal of this proposal is to elucidate the molecular mechanisms that regulate intestinal permeability. Such regulation occurs in vivo as a consequence of transcellular Na+-nutrient transport and may result in paracellular amplification of nutrient absorption. Thus, characterization of the underlying mechanisms will enhance understanding of nutrient absroption and physiologic regulation of intestinal permeability. At the cellular level, the tight junction is the major determinant of paracellular permeability. Both structural and functional tight junction modifications accompany Na+-nutrient, e.g. Na+-glucose, cotransport in intact mucosa. However, the complexities of intact mucosa have limited further analysis of this process. In order to evaluate tight junction regulation in detail I have established a cell culture model of regulated paracellular (tight junction) permeability as a consequence of Na+-glucose cotransport. This proposal will test the hypothesis that Na+-nutrient cotransport initiates a signalling cascade which leads to structural and functional tight junction modifications resulting in augmented paracellular permeability. The proposed signalling pathway leading from Na+-glucose cotransport to altered tight junction permeability will be dissected into a series of sequential events. Additionally, the specific morphologic and biochemical alterations of the tight junction and tight junction-associated proteins that occur as a function of Na+-glucose cotransport will be evaluated. Experimental design will include functional, morhpologic, biochemical, and pharmacologic assessment of tight junctions during Na+-glucose cotransport.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002503-03
Application #
2733832
Study Section
Special Emphasis Panel (SRC)
Program Officer
Podskalny, Judith M
Project Start
1996-09-15
Project End
2001-06-30
Budget Start
1998-09-20
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Wang, Lejin; Wang, Lejing; He, Fei et al. (2012) ABCB6 mutations cause ocular coloboma. Am J Hum Genet 90:40-8
Dailey, Harry A; Septer, Alecia N; Daugherty, Lauren et al. (2011) The Escherichia coli protein YfeX functions as a porphyrinogen oxidase, not a heme dechelatase. MBio 2:e00248-11
Hopper, Tim A J; Wehrli, Felix W; Saha, Punam K et al. (2007) Quantitative microcomputed tomography assessment of intratrabecular, intertrabecular, and cortical bone architecture in a rat model of severe renal osteodystrophy. J Comput Assist Tomogr 31:320-8
Abner, S R; Hill, D E; Turner, J R et al. (2002) Response of intestinal epithelial cells to Trichuris suis excretory-secretory products and the influence on Campylobacter jejuni invasion under in vitro conditions. J Parasitol 88:738-45
Turner, J R; Black, E D (2001) NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)-glucose cotransport in intestinal epithelia. Am J Physiol Cell Physiol 281:C1533-41
Guzman, C B; Walsh, M; Reddy, V et al. (2001) Altered myosin light-chain phosphorylation in resting platelets from premenopausal women with diabetes. Metabolism 50:151-6
Berglund, J J; Riegler, M; Zolotarevsky, Y et al. (2001) Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na(+)-glucose cotransport. Am J Physiol Gastrointest Liver Physiol 281:G1487-93
Furuta, G T; Turner, J R; Taylor, C T et al. (2001) Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med 193:1027-34
Yu, Y; Rishi, A K; Turner, J R et al. (2001) Cloning of a novel EGFR-related peptide: a putative negative regulator of EGFR. Am J Physiol Cell Physiol 280:C1083-9
Turner, J R; Torres, C M; Wang, H H et al. (2000) Preoperative chemoradiotherapy alters the expression and prognostic significance of adhesion molecules in Barrett's-associated adenocarcinoma. Hum Pathol 31:347-53

Showing the most recent 10 out of 19 publications