Brain Research Institute

Aldons Lusis, Ph.D.

Work Email Address:
jlusis@mednet.ucla.edu

Mailing Address:
BH-307 CHS
CAMPUS - 167917
Los Angeles, CA
UNITED STATES

Work Address:
Office
MRL 3-730
Los Angeles, CA 90095
UNITED STATES

Laboratory
MRL
Los Angeles, CA 90095
UNITED STATES

Work Phone Number:
(310) 825-1359

Department / Division Affiliations

Professor, Human Genetics, Medicine, Microbiology, Immunology & Molecular Genetics

Director, Mouse Metabolic Syndrome Phenotype Facility

Faculty, Brain Research Institute, Cardiology

Member, ACCESS Program: Dept. of Microbiology, Immunology, & Molecular Genetics

ACCESS Affinity - Genetics & Genomics

Research Interest:

The analysis of complex genetic diseases

Atherosclerosis, a disease of the large arteries that is the major cause of heart disease and stroke, has a very complex etiology. Although cholesterol levels, diabetes, blood pressure, and a number of other risk factors have been associated with the disease, its primary causes and mechanistic details remain poorly understood. Our lab is using genetic approaches to clarify the molecular and cellular interactions involved in the disease. Through mapping and positional cloning in both human subjects and mouse animal models, we hope to identify new genes and pathways contributing to atherosclerosis. Such gene mapping approaches have revolutionized our understanding of Mendelian diseases, but their application to complex diseases such as atherosclerosis has thus far been disappointing. However, we are optimistic that new resources, particularly the sequences of the human and mouse genomes, and new tools, such as global analysis of transcript levels, will greatly enhance our ability to identify novel genes using positional cloning. We are also using transgenic and gene targeting technologies to examine in detail the interactions contributing to the initiation and progression of the disease. Our research is divided into two general areas, one concerning A?metabolic syndromeA? and the other inflammation and oxidation. A?Metabolic syndromeA? consists of a cluster of metabolic disturbances with insulin resistance as a central feature, and it is strongly associated with coronary heart disease. We have focused on one form of the disease, termed A?familial combined hyperlipidemiaA?, characterized by elevated triglyceride and cholesterol levels. For these studies, we are collaborating with Dr. Tjerk deBruin and his group in the Netherlands, who have collected numerous families with multiple affected individuals. Although we have identified and characterized some genes that modify the familial combined hyperlipidemic phenotype, we have as yet been unable to identify the major genes involved. Some preliminary evidence suggests that the disease may be very heterogeneous, complicating positional cloning approaches. Using mapping strategies in the mouse, we have identified and studied some genes that result in hypertriglyceridemia or insulin resistance, including apolipoprotein AII, thioredoxin inhibitory protein, and 5-lipoxygenase. We are now testing the relevance of these genes in human metabolic syndrome. In studies with mouse models, we have recently made some important finding regarding the role of inflammation and oxidation in atherosclerosis. One very exciting result was the demonstration that genetic differences in atherosclerosis susceptibility in mice are due in part to genetic variation in inflammatory responses of endothelial cells to oxidized lipids. We are now attempting to identify the underlying genes and test whether similar differences occur in human populations. Another important achievement was the identification of 5-lipoxygenase as an important determinant of atherosclerosis susceptibility in mice. Preliminary work suggests that variations of the enzyme may be an important determinant of the disease in humans as well.

Publications:

Warden CH, Hedrick CC, Qiao JH, Castellani LW, Lusis AJ. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science ; 261(5120): 469-72.

Wang S, Yehya N, Schadt EE, Wang H, Drake TA, Lusis AJ. Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet 2006; 2(2): e15.

Gargalovic PS, Imura M, Zhang B, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Patel S, Nelson SF, Horvath S, Berliner JA, Kirchgessner TG, Lusis AJ. Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids. Proc Natl Acad Sci USA 2006; 103(34): 12741-6.

Drake TA, Schadt EE, Lusis AJ. Integrating genetic and gene expression data: application to cardiovascular and metabolic traits in mice. Mamm Genome 2006; 17(6): 466-79.

Ghazalpour A, Doss S, Zhang B, Wang S, Plaisier C, Castellanos R, Brozell A, Schadt EE, Drake TA, Lusis AJ, Horvath, S. Integrating genetic and network analysis to characterize genes related to mouse weight. PLoS Genet 2006; 2(8): .

Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, Drake TA, Lusis AJ. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 2006; 16(8): 995-1004.

Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R, Lusis AJ, Mehrabian M. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 2004; 350(1): 29-37.

Lusis AJ, Mar R, Pajukanta P. Genetics of atherosclerosis. Annu Rev Genomics Hum Genet. 2004; 5: 189-218.

Mehrabian M, Wong J, Wang X, Jiang Z, Shi W, Fogelman AM, Lusis AJ. Genetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia. Circ Res 2001; 89(2): 125-30.

Brennan ML, Anderson MM, Shih DM, Qu XD, Wang X, Mehta AC, Lim LL, Shi W, Hazen SL, Jacob JS, Crowley JR, Heinecke JW, Lusis AJ. Increased atherosclerosis in myeloperoxidase-deficient mice. J Clin Invest 2001; 107(4): 419-30.

Lusis, A.J. Atherosclerosis. Nature 2000; 407: 233-241.

Shi W, Wang NJ, Shih DM, Sun VZ, Wang X, Lusis AJ. Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. Circ Res 2000; 86(10): 1078-84.

Shi W., Haberland M.E., Shih D.M., Jien M-L., Lusis A.J. Differential responses of endothelial cells to oxidized lipoproteins contribute to genetic differences in atherosclerosis in mice . Circulation 2000; 102: 75-81.

Aouizerat BE, Allayee H, Cantor RM, Davis RC, Lanning CD, Wen PZ, Dallinga-Thie GM, de Bruin TW, Rotter JI, Lusis AJ. A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11. Am J Hum Genet 1999; 65(2): 397-412.

Allayee H, Aouizerat BE, Cantor RM, Dallinga-Thie GM, Krauss RM, Lanning CD, Rotter JI, Lusis AJ, de Bruin TW. Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype. Am J Hum Genet. 1998; 63(2): 577-85.

Castellani LW, Weinreb A, Bodnar J, Goto AM, Doolittle M, Mehrabian M, Demant P, Lusis AJ. Mapping a gene for combined hyperlipidaemia in a mutant mouse strain. Nat Genet 1998; 18(4): 374-7.

Ivandic BT, Qiao JH, Machleder D, Liao F, Drake TA, Lusis AJ. A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice. Proc Natl Acad Sci USA 1996; 93(11): 5483-8.

Liao F, Andalibi A, Qiao JH, Allayee H, Fogelman AM, Lusis AJ. Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J Clin Invest. 1994; 94(2): 877-84.

Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 1990; 344(6263): 254-7.

Lusis Aldons J, Attie Alan D, Reue Karen Metabolic syndrome: from epidemiology to systems biology.. Nature reviews. Genetics. 2008; 9(11): 819-30.

van Nas A, Guhathakurta D, Wang SS, Yehya N, Horvath S, Zhang B, Ingram-Drake L, Chaudhuri G, Schadt EE, Drake TA, Arnold AP, Lusis AJ Elucidating the Role of Gonadal Hormones in Sexually Dimorphic Gene Co-Expression Networks.. Endocrinology. 2008; 9(11): .

Ghazalpour Anatole, Doss Sudheer, Kang Hyun, Farber Charles, Wen Ping-Zi, Brozell Alec, Castellanos Ruth, Eskin Eleazar, Smith Desmond J, Drake Thomas A, Lusis Aldons J High-resolution mapping of gene expression using association in an outbred mouse stock.. PLoS genetics. 2008; 4(8): e1000149.

Castellani Lawrence W, Nguyen Cara N, Charugundla Sarada, Weinstein Michael M, Doan Chau X, Blaner William S, Wongsiriroj Nuttaporn, Lusis Aldons J Apolipoprotein AII is a regulator of very low density lipoprotein metabolism and insulin resistance.. The Journal of biological chemistry. 2008; 283(17): 11633-44.

Chen Yanqing, Zhu Jun, Lum Pek Yee, Yang Xia, Pinto Shirly, MacNeil Douglas J, Zhang Chunsheng, Lamb John, Edwards Stephen, Sieberts Solveig K, Leonardson Amy, Castellini Lawrence W, Wang Susanna, Champy Marie-France, Zhang Bin, Emilsson Valur, Doss Sudheer, Ghazalpour Anatole, Horvath Steve, Drake Thomas A, Lusis Aldons J, Schadt Eric E Variations in DNA elucidate molecular networks that cause disease.. Nature. 2008; 452(7186): 429-35.

Wang Susanna S, Schadt Eric E, Wang Hui, Wang Xuping, Ingram-Drake Leslie, Shi Weibin, Drake Thomas A, Lusis Aldons J Identification of pathways for atherosclerosis in mice: integration of quantitative trait locus analysis and global gene expression data.. Circulation research. 2007; 101(3): e11-30.

Shaposhnik Zory, Wang Xuping, Weinstein Michael, Bennett Brian J, Lusis Aldons J Granulocyte macrophage colony-stimulating factor regulates dendritic cell content of atherosclerotic lesions.. Arteriosclerosis, thrombosis, and vascular biology. 2007; 27(3): 621-7.

Meng Haijin, Vera Iset, Che Nam, Wang Xuping, Wang Susanna S, Ingram-Drake Leslie, Schadt Eric E, Drake Thomas A, Lusis Aldons J Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics.. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(11): 4530-5.

Schadt, EE Lamb, J Yang, X Zhu, J Edwards, S Guhathakurta, D Sieberts, SK Monks, S Reitman, M Zhang, C Lum, PY Leonardson, A Thieringer, R Metzger, JM Yang, L Castle, J Zhu, H Kash, SF Drake, TA Sachs, A Lusis, AJ An integrative genomics approach to infer causal associations between gene expression and disease. Nature genetics . 2005; 37(7): 710-7.

Doss, S Schadt, EE Drake, TA Lusis, AJ Cis-acting expression quantitative trait loci in mice. Genome research. 2005; 15(5): 681-91.
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Bodnar, JS Chatterjee, A Castellani, LW Ross, DA Ohmen, J Cavalcoli, J Wu, C Dains, KM Catanese, J Chu, M Sheth, SS Charugundla, K Demant, P West, DB de Jong, P Lusis, AJ Positional cloning of the combined hyperlipidemia gene Hyplip1.. Nature genetics. . 2002; 30(1): 110-6.

Shih, DM Gu, L Xia, YR Navab, M Li, WF Hama, S Castellani, LW Furlong, CE Costa, LG Fogelman, AM Lusis, AJ Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis.. Nature. . 1998; 394(6690): 284-7.