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Department of Pathology, Microbiology, and Immunology

  

 

  Amy S. Major, Ph.D.
 

 

Associate Professor

Dept of Medicine

Dept of Pathology, Microbiology and Immunology

 

  

  Contact Information

 

 

Office Location:

352 PRB

Phone: 615-936-1816

E-mail: amy.major@vanderbilt.edu

Lab Url: https://medschool.vanderbilt.edu/major-lab/

 

Campus Mail address:

Dept of Medicine

Cardiovascular Medicine

383 PRB (6300)

 

US Mailing address:

Dept of Medicine

Cardiovascular Medicine

Vanderbilt University School of Medicine

383 PRB

Nashville, TN 37232-6300

 

 

 

Education

 

 

postdoctoral fellow, Vanderbilt Univ
Ph.D., West Virginia Univ
B.S., Wheeling Jesuit Univ

 

 

Research Keywords

 

 

atherosclerosis, Inflammation, B lymphocytes, T lymphocytes, autoimmunity, immune complexes

 

 

Research Description

 

 

The broad research focus of Dr. Major's laboratory is to understand immunological mechanisms of cardiovascular disease, specifically atherosclerosis. Atherosclerosis is the number one cause of mortality in developed countries and it is known that both lipids and immunity play significant roles. Work performed in her laboratory has significantly impacted our understanding of how the immune system modulates atherosclerosis as well as how dyslipidema and the atherosclerotic environment influence normal immune function.

It is widely accepted that increased circulating cholesterol (especially LDL) and modifications of lipids are the main culprits in the development of atherosclerosis in the general population. However, over the past three decades, increased focus has been on the role of immune cells, such as B cells and particular subsets of T cells, in the atherogenic process. Dr. Major's laboratory is interested in understanding the relationship between normal and abnormal T and B cell biology and atherosclerosis. Specifically, her lab is trying to understand:

- the relative roles of T and B cells in the atherogenic process;
- how autoimmunity (specifically systemic lupus erythematosus, or lupus) exacerbates the atherosclerotic process;
- how the hyperlipidemic environment associated with atherosclerosis affects immune function (specifically T cells, B cells and immune complexes);
- what molecules, typically associated with lipid homeostasis in health, play roles in lymphocyte activation.

The preclinical models that Dr. Major uses in her studies are the mouse model of atherosclerosis (LDL-receptor deficient or apolipoprotein E deficient) and the mouse model of spontaneous lupus (B6.Sle). Both of these animal models of human disease have been greatly characterized and have pathogenic characteristics relevant to their human disease counterparts. Dr. Major has developed and characterized a novel animal model of lupus-accelerated atherosclerosis by reconstituting lethally-irradiated LDL-receptor deficient mice with the hematopoietic cells from lupus-susceptible mice. The result is an animal that develops lupus and lupus-accelerated atherosclerosis very similar to human lupus patients. The proceeding is a brief narrative of Dr. Major's ongoing projects in the laboratory focused on understanding the relationship between normal and abnormal immune function and atherosclerosis.



 

 

Clinical Research Description

 

 

 

 

Publications

 

 

Wilhelm, AJ, Rhoads, JP, Wade, NS, Major, AS. Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Ann Rheum Dis, 2014

Major, AS. Expanding the therapeutic frontier in atherosclerosis. J Cardiovasc Pharmacol, 62(3), 237-8, 2013

Liu, Y, Major, AS, Zienkiewicz, J, Gabriel, CL, Veach, RA, Moore, DJ, Collins, RD, Hawiger, J. Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. J Am Heart Assoc, 2(2), e000093, 2013

van Leuven, SI, Mendez-Fernandez, YV, Wilhelm, AJ, Wade, NS, Gabriel, CL, Kastelein, JJ, Stroes, ES, Tak, PP, Major, AS. Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr(-/-) mice. Ann Rheum Dis, 71(3), 408-14, 2012

Gabriel, CL, Smith, PB, Mendez-Fernandez, YV, Wilhelm, AJ, Ye, AM, Major, AS. Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus. Am J Physiol Endocrinol Metab, 303(11), E1313-24, 2012

Wilhelm, AJ, Major, AS. Accelerated atherosclerosis in SLE: mechanisms and prevention approaches. Int J Clin Rheumtol, 7(5), 527-539, 2012

Mendez-Fernandez, YV, Stevenson, BG, Diehl, CJ, Braun, NA, Wade, NS, Covarrubias, R, van Leuven, S, Witztum, JL, Major, AS. The inhibitory FcI?RIIb modulates the inflammatory response and influences atherosclerosis in male apoE(-/-) mice. Atherosclerosis, 214(1), 73-80, 2011

Ma, LJ, Corsa, BA, Zhou, J, Yang, H, Li, H, Tang, YW, Babaev, VR, Major, AS, Linton, MF, Fazio, S, Hunley, TE, Kon, V, Fogo, AB. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am J Physiol Renal Physiol, 300(5), F1203-13, 2011

Wade, NS, Major, AS. The problem of accelerated atherosclerosis in systemic lupus erythematosus: insights into a complex co-morbidity. Thromb Haemost, 106(5), 849-57, 2011

van Leuven, SI, Mendez-Fernandez, YV, Stroes, ES, Tak, PP, Major, AS. Statin therapy in lupus-mediated atherogenesis: two birds with one stone. Ann Rheum Dis, 70(2), 245-8, 2011

Braun, NA, Mendez-Fernandez, YV, Covarrubias, R, Porcelli, SA, Savage, PB, Yagita, H, Van Kaer, L, Major, AS. Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia. Arterioscler Thromb Vasc Biol, 30(9), 1758-65, 2010

Braun, NA, Covarrubias, R, Major, AS. Natural killer T cells and atherosclerosis: form and function meet pathogenesis. J Innate Immun, 2(4), 316-24, 2010

Wade, NS, Stevenson, BG, Dunlap, DS, Major, AS. The lupus susceptibility locus Sle3 is not sufficient to accelerate atherosclerosis in lupus-susceptible low density lipoprotein receptor-deficient mice. Lupus, 19(1), 34-42, 2010

Wilhelm, AJ, Zabalawi, M, Grayson, JM, Weant, AE, Major, AS, Owen, J, Bharadwaj, M, Walzem, R, Chan, L, Oka, K, Thomas, MJ, Sorci-Thomas, MG. Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity. Arterioscler Thromb Vasc Biol, 29(6), 843-9, 2009

Braun, N, Wade, NS, Wakeland, EK, Major, AS. Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice. Lupus, 17(12), 1070-8, 2008

Overton, CD, Yancey, PG, Major, AS, Linton, MF, Fazio, S. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ Res, 100(5), 670-7, 2007

Major, AS, Joyce, S, Van Kaer, L. Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. Trends Mol Med, 12(6), 270-8, 2006

Major, AS, Singh, RR, Joyce, S, Van Kaer, L. The role of invariant natural killer T cells in lupus and atherogenesis. Immunol Res, 34(1), 49-66, 2006

Stanic, AK, Stein, CM, Morgan, AC, Fazio, S, Linton, MF, Wakeland, EK, Olsen, NJ, Major, AS. Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus. Proc Natl Acad Sci U S A, 103(18), 7018-23, 2006

Burleigh, ME, Babaev, VR, Yancey, PG, Major, AS, McCaleb, JL, Oates, JA, Morrow, JD, Fazio, S, Linton, MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice. J Mol Cell Cardiol, 39(3), 443-52, 2005

Su, YR, Dove, DE, Major, AS, Hasty, AH, Boone, B, Linton, MF, Fazio, S. Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1. Circulation, 111(18), 2373-81, 2005

Major, Amy S, Wilson, Michael T, McCaleb, Jennifer L, Su, Yan Ru, Stanic, Aleksandar K, Joyce, Sebastian, Van Kaer, Luc, Fazio, Sergio, Linton, Macrae F. Quantitative and Qualitative Differences in Proatherogenic NKT Cells in Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol, 2004

Linton, MacRae F, Major, Amy S, Fazio, Sergio. Proatherogenic role for NK cells revealed. Arterioscler Thromb Vasc Biol, 24(6), 992-4, 2004

Su, Yan Ru, Ishiguro, Hiroyuki, Major, Amy S, Dove, Dwayne E, Zhang, Wenwu, Hasty, Alyssa H, Babaev, Vladimir R, Linton, MacRae F, Fazio, Sergio. Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters. Mol Ther, 8(4), 576-83, 2003

Fazio, Sergio, Babaev, Vladimir R, Burleigh, Michael E, Major, Amy S, Hasty, Alyssa H, Linton, MacRae F. Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice. J Lipid Res, 43(10), 1602-9, 2002

Major, Amy S, Fazio, Sergio, Linton, MacRae F. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol, 22(11), 1892-8, 2002

Yoshida, H, Hasty, A H, Major, A S, Ishiguro, H, Su, Y R, Gleaves, L A, Babaev, V R, Linton, M F, Fazio, S. Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice. Circulation, 104(23), 2820-5, 2001

Major, A S, Dove, D E, Ishiguro, H, Su, Y R, Brown, A M, Liu, L, Carter, K J, Linton, M F, Fazio, S. Increased cholesterol efflux in apolipoprotein AI (ApoAI)-producing macrophages as a mechanism for reduced atherosclerosis in ApoAI((-/-)) mice. Arterioscler Thromb Vasc Biol, 21(11), 1790-5, 2001

Ishiguro, H, Yoshida, H, Major, A S, Zhu, T, Babaev, V R, Linton, M F, Fazio, S. Retrovirus-mediated expression of apolipoprotein A-I in the macrophage protects against atherosclerosis in vivo. J Biol Chem, 276(39), 36742-8, 2001

Swift, L L, Farkas, M H, Major, A S, Valyi-Nagy, K, Linton, M F, Fazio, S. A recycling pathway for resecretion of internalized apolipoprotein E in liver cells. J Biol Chem, 276(25), 22965-70, 2001

Fazio, S, Major, A S, Swift, L L, Gleaves, L A, Accad, M, Linton, M F, Farese, R V. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J Clin Invest, 107(2), 163-71, 2001

Major, A S, Rubin, D H, Cuff, C F. Mucosal immunity to reovirus infection. Curr Top Microbiol Immunol, 233(Pt 2), 163-77, 1998

Major, A S, Cuff, C F. Enhanced mucosal and systemic immune responses to intestinal reovirus infection in beta2-microglobulin-deficient mice. J Virol, 71(8), 5782-9, 1997

Major, A S, Cuff, C F. Effects of the route of infection on immunoglobulin G subclasses and specificity of the reovirus-specific humoral immune response. J Virol, 70(9), 5968-74, 1996