Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Medicine

Department

Toxicology

First Advisor

Dr. Mary Vore

Second Advisor

Dr. Arnold Stromberg

Abstract

Rat exon microarrays were utilized to detect changes in mRNA expression and alternative splicing in the liver, duodenum, jejunum, and ileum of the lactating rat when compared to age-matched virgin controls. Analysis of data at the level of gene expression revealed differential expression of genes involved in cholesterol biosynthesis in each tissue examined, suggesting increased Sterol Response Element Binding Protein activity. We also detected decreased mRNA from components of the T-cell signaling pathway in the jejunum and ileum. We characterized expression of solute carrier and adenosine triphosphate binding cassette proteins. In addition to characterizing genes by pathway, we have also grouped genes based on their pattern of expression to identify important genes. Amongst genes upregulated in all tissues was Slc39a4, which is a critical transporter in the absorption of zinc in enterocytes. Alternative splicing analysis detected a substantial amount of alternative splicing in the ileum compared to other tissues. In addition, in the liver Abcg8, a protein that functions as a heterodimer to export cholesterol in the bile, shows differential splicing in the liver, but not in other tissues. We also detected differential expression of Ugt1a6 in the liver based on usage of an alternative first exon, which is consistent with altered protein levels observed previously. Differential splicing also appears to occur in Ace2 in the ileum, which could have consequences on the renin-angiotensin pathway.

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