Aldons J. Lusis Dept. Of Medicine Dept. Of Microbiology, Immunology, and Molecular Genetics Dept. Of Human Genetics UCLA, Los Angeles, CA 90095-1679. Phone: 310-825-1359 Email: jlusis@mednet.ucla.edu

 

Research Interest: Novel Genes and Pathways in Heart Disease

Atherosclerosis, the primary cause of heart disease and stroke, has an important genetic component, but the genes contributing to the common forms of the disease are largely unknown. Studies in humans have been hampered by the etiologic complexity of atherosclerosis. One approach to the problem involves studies in mouse models, which are more amenable to genetic dissection of complex traits. The genes and pathways identified in mice can them be tested in human populations.

Familial combined hyperlipidemia (FCH), characterized by elevated levels of triglyceride and cholesterol, is a common cause of early heart disease. Studies of a mouse model of FCH (Castellani et al. Nature Genetics, 1998) implicates the thioredoxin system, the primary regulator of cellular redox states, in the control of lipid metabolism in liver and muscle. The hyperlipidemia mouse has a defect in a gene, designated Hyplip1, that encodes a thioredoxin-binding protein. A locus contributing to FCH on human chromosome 1q contains the ortholog of the Hyplip1 gene, and we are investigating whether variations of the gene may contribute to the human disorder.

As yet, human studies have not succeeded in identifying genetic factors in atherosclerosis that act by affecting vascular cell functions, a major problem being the difficulty of accurately evaluating the severity of disease by noninvasive techniques. Using genetic studies in mice, we have identified at least two pathways in atherosclerosis that affect cellular functions. Genetic variations affecting these pathways in mice can completely block the development of lesions, even on the background of extreme hyperlipidemia resulting from mutations of apolipoprotein E or the low density lipoprotein receptor. One of the pathways influences endothelial cell responses to oxidized lipoproteins, while the other appears to control interactions with blood cells. Neither pathway has significant effects on cholesterol metabolism, blood pressure or other common risk factors. We are searching for the underlying genes using a combination biochemical, genetic and genomics approaches.

Selected Recent Publications

Lusis A.J., Paigen K. (1975) Genetic determination of the ?-galactosidase developmental program in mice. Cell 6:371-378.

Lusis A.J., Golde D.W., Quon D.H., Lasky L.A. (1982) Translation of mRNA for human granulocyte-macrophage colony stimulating factor. Nature 298:75-77.

Lusis A.J., West R., Mehrabian M., Reuben M.A., LeBoeuf R.C., Kaptein J.S., Johnson D.F., Schumaker V.N., Yuhasz M.P., Schotz M.C., Elovson J. (1985) Cloning and expression of apolipoprotein B, the major protein of low and very low density lipoproteins. Proc. Nat. Acad. Sci. USA 82:4597-4601.

Rajavashisth T., Eng R., Shadduck R.K., Waheed D., Ben-Avram C.M., Shively J.E., Lusis A.J. (1987) Cloning and tissue-specific expression of mouse macrophage colony stimulating factor mRNA. Proc. Nat. Acad. Sci. USA 84:1157-1161.

Rajavashisth T.B., Andalibi A., Territo M.C., Berliner J.A., Navab M., Fogelman A.M., Lusis A.J. (1990) Induction of endothelial cell expression of granulocyte and macrophage colony stimulating factors by modified low density lipoproteins. Nature 344:254-257.

Warden C.H., Hedrick C.C., Qiao J.-H., Castellani L.W., Lusis A.J. (1993) Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science 261:469-472.

Castellani L.W., Weinreb A., Bodnar J., Goto A.M., Doolittle M., Mehrabian M., Demant P., Lusis A.J. (1998) Mapping of a gene for combined hyperlipidemia using a mutant mouse strain. Nature Genet. 18:374-377.

Shih D.M., Gu L., Xia Y-R., Navab M., Li W-F., Hama S., Castellani L.W., Furlong C.E., Costa L.G., Fogelman A.M., Lusis A.J. (1998) Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394:284-287.

Lusis A.J. (2000) Atherosclerosis. Nature 407:233-241.

Bodnar J.S., Chatterjee A., Castellani L.W., Ross D.A., Ohmen J., Cavalcoli J., Wu C., Dains K.M., Catanese J., Chu M., Sheth S.S., Charugundla K., Demant P., West D.B., de Jong P., Lusis A.J. (2002) Positional cloning of combined hyperlipidemia gene Hyplip1. Nat. Genet. 30:110-116.

Schadt E.E., Monks S.A., Drake T.A., Lusis A.J., Che N., Colinayo V. Ruff T.G., Milligan S.B., Lamb J.R., Cavet G., Linsley P.S., Mao M., Stoughton R.B., Friend S.H. (2003) Genetics of gene expression surveyed in maize, mouse and man (with commentary by A. Darvasi on pp. 269-270). Nature 422:297-302.

Links http://www.med.ucla.edu/ (dept. of medicine) http://www.mimg.ucla.edu/ (dept. of MIMG) http://www.genetics.ucla.edu/home/ (dept. of human genetics) http://www.mbi.ucla.edu/ (MBI) http://www.genetics.ucla.edu/GATG/GATG_Faculty.html (GTM stuff) http://www.ucla.edu A. Jake Lusis jlusis@mednet.ucla.edu (310)825-1359