Abstract Apolipoprotein E (apo E) is one of the key regulatory proteins in cholesterol and lipoprotein metabolism. The present research focuses on the role of apo E in gastrointestinal diseases. The polymorphism of apo E has been suggested to be associated with the cholesterol content in gallstones and the crystallization rate of gallbladder bile. The possible effect of apo E polymorphism on the susceptibility to gallstone disease at the population level was examined in comparison with the classical risk factors for gallstone disease. The data suggest that the apolipoprotein E2 isoform is a genetic factor that provides protection against gallstone disease in women. The alterations in plasma lipoprotein levels and bile acid metabolism observed in patients with colorectal adenoma and carcinoma may reflect a genetic background predisposing to tumors through altered lipid metabolism. To determine, whether the polymorphism of apo E is associated with proximal or distal colonic neoplasia, the apo E phenotype was determined in 135 patients with colorectal carcinoma, and 199 randomly selected control subjects. The frequency of the ε4 allele of apo E was low in the patients with proximal adenoma and those with carcinoma, respectively, compared with the control subjects. The patients with distal tumors showed no alteration in ε4 frequency. The data suggest that the ε4 allele of apo E provides protection against the development of adenoma and carcinoma of the proximal colon. The association of apo E polymorphism with tumors is not a generalized phenomenon as is shown by the lack of association with breast or prostate cancers. To further study the mechanisms by which apo E might affect colon cancer, the expression of apo E in human intestine and the localization of apo E in normal and malignant gastrointestinal tract was studied using immunohistochemistry and in situ hybridization. Both immunoreactive apo E protein and apo E mRNA were present throughout the stomach, small intestine and colon. The phagocytes of lamina propria were positive for apo E, but the number of positive cells and the staining intensity varied according to localization. Macrophages in the superficial lamina propria of normal colon were more strongly positive for apo E than those in the small intestine, where the most positively stained cells were dendritic cells and macrophages in the germinal centers of lymphoid follicles. In samples from colorectal carcinomas intensely positive macrophages surrounded the tumor area, suggesting that apo E might play a role in the proliferation of malignant cells. Apo E binds with very high affinity to heparin and proteoglycans and inhibits the proliferation of several cell types, but the antiproliferative mechanism of apo E is still largely unknown. The effects of apo E at the cellular levels were studied in cell culture experiments. The effect of recombinant human apo E3 on cell polarity and the distribution of β-catenin were examined in undifferentiated (G+) and differentiated (G+ reversed) HT29 human colon adenocarcinoma cell lines. In cultured undifferentiated HT29 cells, treatment with apo E improved cell polarity and translocated β-catenin from the cytoplasm to cell-cell adhesion sites. Apo E may thus modulate epithelial integrity and contribute to cell growth and malignant transformation.

The homeodomain transcription factor family of Cdx genes, Cdx1, Cdx2 and Cdx4, are known to play essential roles in many developmental processes including neural tube closure, axial elongation, hematopoiesis and gastrointestinal patterning. In the adult, Cdx1 and Cdx2 are both expressed strictly in the adult intestinal epithelium, but their functions and mechanisms of action at this stage are poorly understood. Cdx transcription factors have also been reported to be lost in intestinal cancers. To circumvent early lethality, a conditional loss of function strategy was used to inactivate Cdx2 in the adult intestinal epithelium. These conditional mutants were crossed to Cdx1-/- mice to examine potential functional compensation between these family members as well as into APC(min/+) mice to study their role in tumorigenesis. Using these models, I have found that Cdx2 regulates adult intestinal homeostasis and differentiation in the small intestinal epithelium, while both Cdx1 and Cdx2 contribute to colon homeostasis. Furthermore, Cdx transcription factors are tumor suppressors in the development of Wnt-induced colorectal cancer, and impact several pathways including TGF-β and Eph-ephrin signaling. Finally, Cdx2 regulates Eph-ephrin signaling through direct activation of the Notch pathway. Altogether, this study underscores critical roles and mechanisms of action for Cdx members in the adult intestine and in intestinal tumorigenesis.

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The development of the intestine and early establishment of commensal bacteria is important for rapid growth and enteric disease resistance of the modern broiler. Three studies measured the impact of yeast derivatives in diets of broilers. The objective of the first study was to determine if yeast products alone or in combination effected performance or gut morphology of broilers during a mild coccidia challenge. Day-old Cobb 500 chicks were placed in floor pens on litter seeded with coccidia and fed diets with or without yeast products. The objectives of the second and third studies were to 1) evaluate the effect of feeding cecal droppings collected from heavy (HW) or low weight (LW) broilers on performance and 2) to determine if dietary supplementation with yeast derivatives would effect growth and gut morphology in broilers fed the cecal droppings from HW or LW populations. Cobb 500 chicks were divided into two groups (HW or LW microflora; n=1400/group) and given access to the cecal droppings for a period of 48 hours then given 1 of 4 diets. The results from the studies showed that in a challenge setting, yeast products were not detrimental to growth. Inclusion of single yeast derivative or nucleotides was more beneficial than combination of these products for intestinal morphology. Cecal droppings from HW vs. LW birds did not have an effect on performance of birds. However, interactions of cecal dropping source and diet did affect intestinal morphology. / Master of Science

Erratum is pasted onto back end-paper. / Bibliography: leaves 164-207. / xvii, 207, [26] leaves, [23] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Explores the hypothesis that physiological inflammation in the small intestine and the mesenteric lymph node is upregulated during the weaning period. Aims to determine changes in the number, phenotype, and activation status (using interleukin-2 receptor expression) of intraepithelial lymphocytes, lamina propria lymphocytes, mucosal mast cells, and mesenteric lymph node cells from preweaning to post weaning rats. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1998

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Thesis (Ph.D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (April 25, 2007) Vita. Includes bibliographical references.