McNamara, Coleen A.
Professor of Medicine/Cardiovascular Division, Beirne B. Carter Professor of Immunology and Director of the Beirne B. Carter Center for Immunology Research, Medicine: Cardiovascular Medicine
- Fellowship, Cardiovascular Medicine, University of Virginia
- MD, , Medical College of Ohio
- Residency, Internal Medicine, University of Virginia
Biotechnology, Cardiovascular Biology, Immunology, Molecular Biology, Physiology, Translational Science
Immune System Regulation of Cardiometabolic Disease
Specific Research Ongoing in the McNamara lab
Discovery of a single nucleotide polymorphism (SNP) in the human ID3 gene that is functionally relevant and associated with vascular disease in humans. The McNamara lab utilized three human cohorts with CAD imaging and found that in all 3 cohorts, a SNP in the Id3 gene at rs11574 was significantly associated with CAD. They further performed biochemical analysis of the Id3 proteins encoded by the common versus the disease-associated (risk) allele and demonstrated that the Id3 protein encoded by the risk allele had a significantly attenuated ability to bind and antagonize its partner protein resulting in altered gene expression (Circ Res) . Discovering the ways that this protein protects from CAD has the potential to lead to new and innovative precision approaches to CAD diagnosis, prevention and treatment.
Id3 Regulates B-1b and Marginal Zone B (MZB) cells to protect from CVD
The McNamara lab discovered that the B-1b B cell subset in mice and the MZB subtype in humans produces abundant atheroprotective natural IgM to oxidation specific epitopes (OSE) on LDL and protects from diet-induced atherosclerosis and inflammation in pre-clinical models. Id3 is a key molecular regulator of both of these subtypes. Single cell analysis of humans referred for coronary artery imaging and use of humanized murine systems have allowed us to unveil the key role for MZB in atheroprotective IgM production in humans. Projects are ongoing to identify the molecular and cellular mechanisms and key Id3 target genes (RNAseq, ChIPseq, etc.) responsible for mediating these effects and developing ways to modulate these genes. The McNamara lab is one of 6 international groups (UVA, Harvard, Mt. Sinai, Cambridge (UK), Karolinska (Sweden), Medical University of Vienna (Austria) funded by the Leducq Foundation to lead the field in dissecting the role of B lymphocytes in CVD.
Other Id3 targets in CVD (Chemokine Receptors)
One Id3 target with strong links to CVD are chemokine receptors. Utilizing flow and mass cytometry assessment of circulating immune cells from subjects with intravascular ultrasound with virtual histology (IVUS-VH) assessment of CAD. we have discovered that the amount of key chemokine receptors (CXCR4 and CCR6) on B-1 cells marks those with low amounts of artery plaque and characteristics that are associated with risk for heart attack. This project is part of an NIH funded Program Project Grant in collaboration with researchers in San Diego, La Jolla and the Medical College of Georgia . We are also currently combining genetics with nanomedicine to develop personalized approaches for immune strategies targeting B-1 cell chemokine receptor expression.
Immune Checkpoint molecules in CVD
The McNamara laboratory is part of another 5 year Leducq Transatlantic Network of Excellence (TNE) to study the role of checkpoint molecular in CVD. Checkpoint inhibitors have revolutionized the therapy of cancer and other immune-mediated diseases. Yet, despite preclinical studies identifying roles for checkpoint molecules in CVD, our understanding of how these molecules and therapies that target them impact human CVD is poorly understood. Together with investigators from the Mayo Clinic, Dartmouth, University of Oxford (UK), Lund University (Sweden), Leiden Academic Center for Drug Research (Netherlands), and Radboud University (Netherlands), the McNamara laboratory at UVA is working to unravel the impact of checkpoint molecules on CVD.
IgE to alpha-gal and CVD
In collaboration with Jeff Wilson and Thomas Platts-Mills at UVA, the McNamara lab recently reported (ATVB) that IgE to α-Gal, the primary cause of delayed anaphylaxis to red meat (α-Gal syndrome), was associated with increased atheroma burden and plaques with more unstable features as measured by IVUS-VH in 118 subjects presenting to UVA for coronary artery imaging. In the United States sensitization to α-Gal is recognized as a consequence of bites of the tick Amblyomma americanum. In collaboration with Dr. Loren Erickson in the Carter Immunology Center, the McNamara lab is now performing further studies to expand these findings and identify the mechanisms mediating these effects through a 5 year grant from the NIH.
The McNamara lab is using precision medicine approaches to also contribute to our knowledge of the broader impact of the immune system on CVD. They have developed the pipeline for high dimensional analysis of human PBMCs to identify unique immunophenotypes associated with disease burden and therapeutic responses. They are applying these innovative systems to clinical scenarios to aid in the development of personalized approaches to therapy. Current studies are focusing on studying human immune subtypes activated by IL-1β and IL-6 in subjects with systolic heart failure receiving IL-1β receptor antagonism or placebo and in subjects with advanced coronary artery imaging to quantitate plaque volume and progression. This work is supported by a Prominence to Preeminence (P2PE) Award from the University of Virginia.