Date of Award

2010

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Smith, Jonathan

Subject Headings

Diseases -- Genetics, Atherosclerosis, Diabetes, Gene expression, Genomics

Abstract

The overall goal of our research was to study and identify genes involved in the development of complex diseases in mice and humans through integrative genetic/genomic approaches. Two complex diseases were the focus of research, atherosclerosis and type 2 diabetes. Mouse models of atherosclerosis, in which the genetic background and the environment can be controlled for, were used to identify and validate atherosclerosis modifier genes. We studied an atherosclerosis quantitative trait locus (QTL) on the distal end of chromosome 5, called Ath24, and generated interval-specific congenic mice on the atherosclerosis resistant AKR and susceptible DBA/2 apoE-deficient strains. To date we have not validated this locus. Because the congenic mice were on pure parental backgrounds we cannot account for strain dependent gene-gene interactions present in the F2 cohort used to identify Ath24 and thus, we are currently generating congenic mice for the Ath24 QTL on the F1 background. A major goal of this research was to confirm or exclude Pan3 as the atherosclerosis modifier gene responsible for the Ath24 QTL, and/or identify new candidate genes. Strain differences in Pan3 sequence and splicing were characterized. Pan3 hemizygous mice on the DBA/2 apoE-deficient background were generated but we observed no significant differences in lesion size when compare to wild type mice. We are currently assessing the effect of Pan3 partial deficiency on the F1 background. We studied the in vitro effect of cholesterol loading on the transcriptome of AKR and DBA/2 macrophages. 265 acetylated-LDL regulated transcripts with significant strain interaction effects were identified. Three transcripts, Alox5ap, Hmgb1 and Por, map to the Ath24 locus and were identified as plausible candidates for this QTL. Also, a pilot study was performed to investigate the effects of bariatric surgery on whole blood gene expression profiles in obese subjects with type 2 diabetes. The expression levels of 200 unique genes were significantly altered after bariatr

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