The objective of this proposal is to investigate whether intestinal basement membrane (BM) pathology in diabetes mellitus plays a role in the development of precocious epithelial maturation and nutrient hyperabsorption. Although this hypothesis has not thus far been explored, this proposal is founded on a large body of preliminary data supporting its formulation. The first phase of this study will be a rigorous analysis of immediate and long-term intestinal adaptive changes in steptozocin-treated, diabetic rats. Specific issues that have been ambiguous in the past such as time course of development, reversibility with insulin, and underlying causative cellular mechanisms will be addressed. Ultrastructural, biochemical, morphometric, functional and molecular findings will be correlated. In the second phase of these studies, the role of basement membrane in diabetic intestinal adaptation will be examined. The immediate and chronic effects of diabetes on morphological, biochemical, compositional and regional features of BM will be defined and correlated with the developments of intestinal adaptive events. How specific modifications of BM or BM constituents seen in diabetes might affect intestinal cell (rat IEC-6 crypt) growth and differentiation will be investigated. Finally, how diabetes might alter specific cellular and molecular mechanisms for 1) biosynthesis and maintenance of BM, and 2) the expression of mature intestinal cell function. With respect to the latter, the level of gene expression of Na-dependent glucose transport and alkaline phosphatase will be investigated by measuring steady state mRNA concentrations. 3) Expression of the laminin receptor, a potentially important component of intestinal epithelial maturation. These studies are significant because they address a previously unexplored mechanism for diabetic intestinal adaptation. In addition, the process of diabetic intestinal adaptation may be a useful paradigm for understanding basic mechanisms of cellular growth and morphogenesis. Such knowledge may be of potential significance to future strategies for treating malabsorption states, where induction of such adaptive processes would be of great benefit. In addition, they may provide insight into mechanisms of neoplastic development and its regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK040922-01
Application #
3241386
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Musch, Mark W; Walsh-Reitz, Margaret Mary; Chang, Eugene B (2006) Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption. Am J Physiol Gastrointest Liver Physiol 290:G222-31
Wilson, K T; Xie, Y; Musch, M W et al. (1993) Sodium nitroprusside stimulates anion secretion and inhibits sodium chloride absorption in rat colon. J Pharmacol Exp Ther 266:224-30
Tamai, H; Gaginella, T S; Kachur, J F et al. (1992) Ca-mediated stimulation of Cl secretion by reactive oxygen metabolites in human colonic T84 cells. J Clin Invest 89:301-7
Hoffman, L R; Chang, E B (1992) Altered regulation of regional sucrase-isomaltase expression in diabetic rat intestine. Am J Physiol 262:G983-9
Musch, M W; Drabik-Arvans, D; Rao, M C et al. (1992) Bethanechol inhibition of chicken intestinal brush border Na/H exchange: role of protein kinase C and other calcium-dependent processes. J Cell Physiol 152:362-71
Hoffman, L R; Yen, S; Chang, E B (1992) Regional alterations in intestinal sucrase expression in streptozocin-treated chronically diabetic rats. Dig Dis Sci 37:1078-83
Chang, E B; Musch, M W; Drabik-Arvans, D et al. (1991) Phorbol ester inhibition of chicken intestinal brush-border sodium-proton exchange. Am J Physiol 260:C1264-72
Hoffman, L R; Chang, E B (1991) Determinants of regional sucrase-isomaltase expression in adult rat small intestine. J Biol Chem 266:21815-20
Semrad, C E; Cragoe Jr, E J; Chang, E B (1990) Inhibition of Na/H exchange in avian intestine by atrial natriuretic factor. J Clin Invest 86:585-91
Chang, E B; Musch, M W (1990) Calcium mediated neurohumoral inhibition of chicken enterocyte Na influx: role of phosphatidylinositol metabolites. Life Sci 46:1913-21

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