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Genetics and Genomics of Complex Diseases;Mouse Atherosclerosis Modifier Genes and Human Gene Expression After Bariatric Surgery

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Genetics and Genomics of Complex Diseases;Mouse Atherosclerosis Modifier Genes and Human Gene Expression After Bariatric Surgery Cleveland State University EngagedScholarship@CSU ETD Archive 2010 Genetics and Genomics of Complex Diseases;Mouse Atherosclerosis Modifier Genes and Human Gene Expression After Bariatric Surgery Stela Z. Berisha Cleveland State University Follow this and additional works at: https://engagedscholarship.csuohio.edu/etdarchive Part of the Biology Commons How does access to this work benefit ou?y Let us know! Recommended Citation Berisha, Stela Z., "Genetics and Genomics of Complex Diseases;Mouse Atherosclerosis Modifier Genes and Human Gene Expression After Bariatric Surgery" (2010). ETD Archive. 33. https://engagedscholarship.csuohio.edu/etdarchive/33 This Dissertation is brought to you for free and open access by EngagedScholarship@CSU. It has been accepted for inclusion in ETD Archive by an authorized administrator of EngagedScholarship@CSU. For more information, please contact [email protected]. GENETICS AND GENOMICS OF COMPLEX DISEASES: MOUSE ATHEROSCLEROSIS MODIFIER GENES AND HUMAN GENE EXPRESSION AFTER BARIATRIC SURGERY STELA Z. BERISHA Bachelor of Science in Biology The University of Tirana June, 1998 Master of Science in Cellular and Molecular Biology The University of Tirana August, 2005 submitted in partial fulfillment of requirements for the degree DOCTOR OF PHILOSOPHY IN REGULATORY BIOLOGY at the CLEVELAND STATE UNIVERSITY August 2010 ©COPYRIGHT BY STELA Z. BERISHA 2010 This dissertation has been approved for the Department of BIOLOGICAL, GEOLOGICAL AND ENVIRONMENTAL SCIENCES and for the College of Graduate Studies of Cleveland State University by _______________________________________________Date: Jonathan D. Smith, Ph.D., Cell Biology /Cleveland Clinic Major Advisor _______________________________________________Date: Roy L. Silverstein, M.D., Cell Biology /Cleveland Clinic Advisory Committee Member _______________________________________________Date: Crystal M. Weyman, Ph.D., BGES /Cleveland State University Advisory Committee Member _______________________________________________Date: Barsanjit Mazumder, Ph.D., BGES /Cleveland State University Advisory Committee Member _______________________________________________Date: Clemencia Colmenares, Ph.D., Cancer Biology/Cleveland Clinic Internal Examiner _______________________________________________Date: David Serre, Ph.D., Genomic Medicine Institute/Cleveland Clinic External Examiner ACKNOWLEDGEMENTS I would like to express my gratitude and to thank every one who made this possible and supported me throughout this long journey. I am very grateful for the constructive criticism and continuous guidance of my major advisor Dr. Jonathan Smith. I am thankful for his patience, encouragement and support throughout these years. I am grateful and would like to thank my advisory committee members, Drs. Roy Silverstein, Crystal Weyman, and Barsanjit Mazumder for their guidance, instructions and encouragement. I would like to thank Dr. David Serre for his valuable help in performing Nested ANOVA analysis and his advice on other statistical analyses. Also, I thank Sangeeta Kashyap and Philip Schauer for providing us with the human samples and clinical data to study the effect of bariatric surgery on the whole blood transcriptome. I am thankful to Smith lab members I had the opportunity to work with throughout these years for their continuous professional help and support. Special thanks to Dr. Peggy Robinet for the courtesy in allowing to use some of her data on cholesterol loading, to Jeffrey Hsu for helping me analyzing the RNA sequencing data and, to Brandon DuGar for his invaluable help in quantifying mouse aortic lesions. A very special thank you goes to my family in Albania for their unconditional love and unlimited support, and for the many sacrifices they went through to see me where I stand today. I am graciously thankful to my best friend in life, who stood beside me throughout these years, for his unconditional love, understanding and trust in me. I can’t find the words to thank him enough for his sacrifices and support. Finally, I would like to thank my friends for their love, encouragement and being there for me whenever I needed them. GENETICS AND GENOMICS OF COMPLEX DISEASES: MOUSE ATHEROSCLEROSIS MODIFIER GENES AND HUMAN GENE EXPRESSION AFTER BARIATRIC SURGERY STELA Z. BERISHA 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 v 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 bariatric surgery, and seven of these transcripts were strongly correlated with the changes in body weight and fasting plasma glucose. Our preliminary data suggest that whole blood expression levels of specific transcripts may be useful as biomarkers for type 2 diabetes and/or therapeutic response. vi TABLE OF CONTENTS Page ABSTRACT ...................................................................................................................... v LIST OF FIGURES……………………………………………………………………...x LIST OF TABLES……………………………………………………………………..xiii LIST OF ABBREVIATIONS…………………………………………………………xiv CHAPTERS I. INTRODUCTION..…………………………….……………………………………1 I.1. Complex Traits and Diseases………………………………………….………….1 I.2. Genetic Studies of Human Complex Diseases…………………………………...2 I.2.1. Family-based genetic linkage analysis…………………………………….2 I.2.2. Genome wide association studies…………………………………………3 I.3. Advantages of Using Mouse Models to Study Genetics of Complex Diseases….8 I.4. Quantitative Trait Locus (QTL) Analysis……………………………………….12 I.4.1. QTL mapping…………………………………………………………….13 I.4.2. QTL confirmation………………………………………………………..14 I.4.3. Fine mapping of a confirmed QTL interval……………………………...16 I.4.4. Alternative approaches to identifying causative genes………………….17 I.4.5. Applying the knowledge gained from mouse studies to human diseases..20 I.5. Dissertation Research Goals…………………………………………………….21 I.6. References…………………………………………………………………….....23 II. PHENOTYPIC STUDIES IN Ath24 QTL CONGENIC MICE………………....28 Introduction…………………………………………………………………………..28 vii Materials and Methods……………………………………………………………….33 Results………………………………………………………………………………..38 Discussion……………………………………………………………………………47 References……………………………………………………………………………49 III. STRUCTURAL STUDIES OF PAN3 GENE IN AKR AND DBA/2 INBRED MOUSE STRAINS AND THE ASSESSMENT OF PAN3 PARTIAL DEFICIENCY EFFECT ON DEVELOPMENT OF ATHEROSCLEROSIS IN FEMALE MICE…………………………………………………………………….52 Introduction…………………………………………………………………………..52 Materials and Methods……………………………………………………………….57 Results………………………………………………………………………………..76 Discussion……………………………………………………………………………99 References……………………………………………………………………….….104 IV. CHARACTERIZATION OF CHOLESTEROL (AcLDL) LOADING EFFECT ON THE GENE EXPRESSION IN BONE MARROW DERIVED MACROPHAGES OF AKR AND DBA/2 ApoE-DEFICIENT MICE…….…..108 Introduction…………………………………………………………………………108 Materials and Methods……………………………………………………………...112 Results………………………………………………………………………………115 Discussion…………………………………………………………………………..130 References.………………………………………………………………………….140 viii V. RESOLUTION OF TYPE 2 DIABETES FOLLOWING BARIATRIC SURGERY IS ASSOCIATED WITH CHANGES IN WHOLE BLOOD GENE EXPRESSION IN A PILOT STUDY.....................................................................143 Abstract……………………………………………………………………………..143 Introduction…………………………………………………………………………145 Materials and Methods……………………………………………………………...146 Results………………………………………………………………………………149 Discussion…………………………………………………………………………..158 References…………………………………………………………………………..164 VI. GENERAL CONCLUSIONS……..………………………………………………..167 APPENDICES ix LIST OF FIGURES Page Figure 2.1: Presentation of Ath24 QTL in a genetic map for the chromosome 5……38 Figure 2.2: Schematic representation
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