In recent years, obesity and diabetes have reached epidemic proportions. These diseases have many health consequences including stroke, heart attack and peripheral vascular disease. Common to all of these is atherosclerosis, which is the process by which lipids, cells and fibrous elements accumulate within the walls of arteries. Coordinated gene expression is essential to maintain normal vascular tissue structure and function and many transcription factors regulate these processes. Our lab has identified the transcription factor Id3 as a major regulator of atherosclerosis and obesity. Our research currently focuses on these two areas, each of which includes several exciting projects:
Project 1: Id3 regulation of immune cell responses in atherosclerosis.
A variety of immune cells influence the development of atherosclerosis, including macrophages, T cells and B cells. While the role of B lymphocytes in atherosclerosis is understudied, they are generally thought to play a protective role. Using animal models, our lab has demonstrated that Id3 regulates the homing of B cells to the vasculature and that the loss of Id3 results in increased plaque formation. In ongoing research, we are utilizing different molecular imaging modalities to further explore and quantify the trafficking of labeled cells to the vessel wall using intravital confocal microscopy, microSPECT/CT, and real-time imaging of cellular trafficking using a gamma camera. In addition, we hope to further elucidate the mechanism by which Id3 affects the function of these cells in disease.
Project 2: Id3 SNPs are associated with atherosclerosis.
Through strong collaborations with the UVA Center for Public Health Genomics, our lab is studying several SNPs that have been associated with various markers of atherosclerosis in diabetic and atherosclerotic populations. In ongoing research, we are determining the mechanism by which these SNPs alter Id3 function in order to understand how they might influence disease progression.
Project 3: Id3 regulation of adipose distribution and adipocyte function.
Studies from our lab have shown an important role for Id3 in the regulation of visceral adiposity in the mouse model. We have also demonstrated the role of Id3 in the transcriptional regulation of adiponectin (an anti-inflammatory cytokine produced by adipocytes). Further studies are underway to investigate the role of Id3 in the proliferation and differentiation of adipocytes and the role of Id3 in adipocyte function.
La Jolla Institute of Allergy & Immunology (LIAI)
Dr. McNamara's project titled, "B-1A Lymphocytes in Atherosclerosis" hypothesizes that Id3 in B cells is necessary for B-la cell atheroprotection through promoting B-la cell cycle progression and self-renewal resulting in increased levels of atheroprotective natural antibodies such as E06. Our lab is currently studying the molecular and cellular mechanisms mediating these effects. Moreover, we are attempting to translate these novel findings in mice into testable hypotheses in humans with type 2 diabetes (T2DM). Through collaborations with our colleagues in La Jolla, and our human core, we are uniquely poised to test these innovative hypotheses to identify molecular mechanisms regulating atheroprotective B cells in mice and humans, potentially leading to identification of novel biomarkers and novel strategies to bolster innate immune protection against atherosclerosis.
Dr. McNamara directs the Human Phenotyping and Immune Cell Core which provides human and immune cell phenotyping critical to the translation of mechanistic findings into the human model.
The effects of immune cell variations on atherosclerosis in humans represents a poorly understood area of atherogenesis and possible atheroprotection. The goal of the Human Phenotyping and Immune Cell Core is to provide the resources necessary for translation of novel immune mechanisms of atherosclerosis that are well defined in murine models into the human model.
Robert M. Berne Cardiovascular Research Center (aka CVRC)
Department of Cardiovascular Medicine
Cardiovascular Training Grant (CVTG and Facebook)
Bosterbio offers an exclusive 20% discount to the McNamara lab and its associates for ELISA kits.
B cells in adventitia of aged ApoE-/- mice: Aorta tertiary lymphoid organs (ATLOs) develop in adventitia of aorta adjacent to atherosclerotic plaque in aged ApoE-/- mice. Immunofluorescence staining with an anti-CD20 antibody in diseased aorta with lymph node demonstrates B cells in the ATLO and renal lymph node (RLN), but not in the media (M) or plaque (P). Yellow line box (left side) indicates enlarged picture of ATLOs (right side). DAPI used for nuclear staining. L= lumen of aorta, A= adventitia of aorta.
Use of Flow Cytometry Identifies Increased Number of B1b B cells in Mice with specific B cell deletion of Id3. Representative flow cytometry plots from PerC of Id3WT and Id3BKO mice. B-2 cells are defined as CD19+B220high, B-1a cells are defined as CD19highB220mid/lowIgMhighCD5+, B-1b cells are defined as CD19highB220mid/lowIgMhighCD5-
Manichaikul A, Rich SS, Perry H, Yeboah J, Law M, Davis M, Parker M, Ragosta M, Connelly JJ, McNamara CA, Taylor AM, A functionally significant polymorphism in ID3 is associated with human coronary pathology., 2014; PloS one. 9(3) e90222. PMID: 24603695 | PMCID: PMC3946163
Perry HM, Oldham SN, Fahl SP, Que X, Gonen A, Harmon DB, Tsimikas S, Witztum JL, Bender TP, McNamara CA, Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation., 2013; Arteriosclerosis, thrombosis, and vascular biology. 33(12) 2771-9. PMID: 24115031 | PMCID: PMC4003558
Perry HM, McNamara CA, Refining the role of B cells in atherosclerosis., 2012; Arteriosclerosis, thrombosis, and vascular biology. 32(7) 1548-9. PMID: 22699274
Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA, Lymphocytes and the adventitial immune response in atherosclerosis., 2012; Circulation research. 110(6) 889-900. PMID: 22427326 | PMCID: PMC3373006
Perry HM, Bender TP, McNamara CA, B cell subsets in atherosclerosis., 2012; Frontiers in immunology. 3() 373. PMID: 23248624 | PMCID: PMC3518786
Lipinski MJ, Campbell KA, Duong SQ, Welch TJ, Garmey JC, Doran AC, Skaflen MD, Oldham SN, Kelly KA, McNamara CA, Loss of Id3 increases VCAM-1 expression, macrophage accumulation, and atherogenesis in Ldlr-/- mice., 2012; Arteriosclerosis, thrombosis, and vascular biology. 32(12) 2855-61. PMID: 23042815 | PMCID: PMC3509414
Bourque JM, Schietinger BJ, Kennedy JL, Pearce EA, Christopher JM, Taylor AM, McNamara CA, Kramer CM, Usefulness of cardiovascular magnetic resonance imaging of the superficial femoral artery for screening patients with diabetes mellitus for atherosclerosis., 2012; The American journal of cardiology. 110(1) 50-6. PMID: 22459304 | PMCID: PMC3377855
Doran AC, Lipinski MJ, Oldham SN, Garmey JC, Campbell KA, Skaflen MD, Cutchins A, Lee DJ, Glover DK, Kelly KA, Galkina EV, Ley K, Witztum JL, Tsimikas S, Bender TP, McNamara CA, B-cell aortic homing and atheroprotection depend on Id3., 2011; Circulation research. 110(1) e1-12. PMID: 22034493 | PMCID: PMC3253259
Cutchins A, Harmon DB, Kirby JL, Doran AC, Oldham SN, Skaflen M, Klibanov AL, Meller N, Keller SR, Garmey J, McNamara CA, Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion., 2011; Arteriosclerosis, thrombosis, and vascular biology. 32(2) 317-24. PMID: 22075252 | PMCID: PMC3262109
Deliri H, Meller N, Kadakkal A, Malhotra R, Brewster J, Doran AC, Pei H, Oldham SN, Skaflen MD, Garmey JC, McNamara CA, Increased 12/15-lipoxygenase enhances cell growth, fibronectin deposition, and neointimal formation in response to carotid injury., 2010; Arteriosclerosis, thrombosis, and vascular biology. 31(1) 110-6. PMID: 20947825
Doran AC, Lehtinen AB, Meller N, Lipinski MJ, Slayton RP, Oldham SN, Skaflen MD, Yeboah J, Rich SS, Bowden DW, McNamara CA, Id3 is a novel atheroprotective factor containing a functionally significant single-nucleotide polymorphism associated with intima-media thickness in humans., 2010; Circulation research. 106(7) 1303-11. PMID: 20185798 | PMCID: PMC2860382
Lipinski MJ, Perry HM, Doran AC, Oldham SN, McNamara CA, Comment on "Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis"., 2010; Journal of immunology (Baltimore, Md. : 1950). 186(1) 4; author reply 6. PMID: 21172871