Molecular regulators of marginal zone B cells in atherosclerosis

University Of Virginia, Charlottesville VA

Investigators

Abstract

Project Summary and Abstract: Atherosclerosis (AS), the most common cause of cardiovascular disease (CVD), is well established as a disease of chronic inflammation. B cells are known to regulate AS in both mice and humans, largely through the production of protective IgM to oxidation specific epitopes (IgMOSE). Recently, novel results from our lab have revealed marginal zone B cells (MZBs) are the main producers of protective IgMOSE in humans. However, the molecular mechanisms that regulate MZBs and their protective function in AS are unknown. Inhibitor of differentiation 3 (Id3) is known to regulate MZB differentiation and is of particular importance to AS. We have shown that a function-attenuating SNP in the human ID3 gene rs11574 is strongly associated with increased AS burden and adverse CVD events. Yet, how Id3 or the ID3 SNP regulates MZB functions in AS remains unknown. Studies in this fellowship proposal seek to determine how Id3 regulates MZB function in AS. Building upon preliminary data that Id3 deficiency in mice alters B cell composition, Aim 1 will determine whether MZBs from B-cell specific Id3 knockout mice have altered proliferation and/or apoptosis. Aim 2, in collaboration with Dr. Meri Nus, addresses whether MZB-specific Id3 deficiency accelerates diet-induced AS. We will create MZB-specific Id3KO LDLR-/- mice, induce diet-induced AS and analyze AS lesion burden and composition. Finally, in aim 3, I will test the role of ID3 SNP in human MZBs. In collaboration with Dr. Justin Taylor, I will use CRISPR-Cas9 editing to introduce rs11574 into human B cells and assess proliferation and antibody production. Additionally, I will use high-dimensional flow cytometry determine if rs11574 is associated with changes in MZB frequency, plasma antibody titers and coronary artery disease (CAD). These human translational studies have the potential to provide a unique genetic biomarker of MZB function in limiting CAD in humans. Importantly, this fellowship proposal outlines a comprehensive training plan for the applicant. Together with the institutional support of the UVA MSTP, Dr. McNamara's close mentorship and training environment support both the applicant's scientific and career development. In addition to training in murine mechanistic studies, the applicant will gain exposure to translational research and physician-scientist mentors through the UVA iPRIME initiative. Furthermore, the collaborations proposed provide the applicant with substantial training opportunities highly complementary to the mentor's training and support, enabling the applicant to propose a stronger research strategy without being overly ambitious. In summary, the applicant will benefit immensely from a well-rounded training program designed to prepare him for upcoming training transitions and a career as a physician-scientist.