# Molecular regulators of marginal zone B cells in atherosclerosis

> **NIH NIH F30** · UNIVERSITY OF VIRGINIA · 2024 · $38,198

## 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.

## Key facts

- **NIH application ID:** 10998154
- **Project number:** 1F30HL176083-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Brett Ransegnola
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,198
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998154

## Citation

> US National Institutes of Health, RePORTER application 10998154, Molecular regulators of marginal zone B cells in atherosclerosis (1F30HL176083-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10998154. Licensed CC0.

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