# Identifying, Characterizing, and Targeting Regulators of B Cell Activation

> **NIH NIH DP5** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $403,750

## Abstract

PROJECT SUMMARY/ABSTRACT
 B cell signaling is responsible for the generation of humoral immunity. It is initiated when an antigen binds
to a cell surface B cell receptor (BCR), triggering a signaling pathway that culminates in the secretion of
neutralizing antibodies. A critical aspect underlying the B cell response to an antigen is the strength of the signal
transmitted through the BCR, which is carefully regulated by various co-receptors in the B cell membrane.
Aberrant BCR signaling is closely associated with B cell dysfunction, including autoimmunity, B cell
malignancies, and immunodeficiency. Therefore, studying the regulatory mechanisms of BCR signaling by co-
receptors is needed to understand B cell immunity, how B cell-derived diseases arise, and will enable selective
targeting of malignant, autoreactive B cells to improve current therapeutics that cause severe
immunosuppression through global depletion of both normal and pathological B cells.
 This project will focus on the primary stimulatory B cell co-receptor, CD19, and will elucidate and
characterize the dynamic regulatory components it coordinates with during B cell activation. CD19 has an
essential role in regulating the initiation of B cell signaling, and it is among the most important immunotherapy
targets, meaning the results from this research program will inform both basic B cell biology and the design of
novel B cell targeting therapeutics. A significant challenge in studying B cell signaling is identifying and
characterizing dynamic regulatory complexes. To overcome this, we will leverage our expertise in structural
biology, protein engineering, and cell biology to develop new cell-based and protein tools to study these dynamic
complexes, allowing us to develop a mechanistic understanding of how CD19 coordinates with accessory co-
receptor components to control the strength of the signal transmitted through the BCR. This will be achieved
through three specific aims. First, we will identify and functionally characterize novel regulators of early B cell
signaling through CD19 proximity labeling coupled to quantitative, multiplexed mass spectrometry (Aim 1). Then,
we will determine the structure of a CD21-CD19 complex, which, combined with functional signaling assays, will
elucidate how the strength of BCR signaling is regulated in response to antigen binding (Aim 2). Finally, we will
engineer cell-state-specific, modulatory antibodies that stabilize the CD19-CD81 complex on resting B cells to
attenuate the immune response to antigen (Aim 3). This proposed research will elucidate the biochemical and
structural basis of regulation of CD19 signaling, identify new regulatory signaling proteins, and develop new ways
of selectively targeting and modulating autoreactive B cell function.

## Key facts

- **NIH application ID:** 10933413
- **Project number:** 5DP5OD036136-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Katherine Julia Susa
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933413

## Citation

> US National Institutes of Health, RePORTER application 10933413, Identifying, Characterizing, and Targeting Regulators of B Cell Activation (5DP5OD036136-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10933413. Licensed CC0.

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