# Functional roles of lipid domains in B cell signaling

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $292,046

## Abstract

PROJECT SUMMARY
B cells sense and manipulate the lateral organization of numerous cell surface receptors in order to facilitate
their functional roles within the immune system. Receptor clustering as a physical mode of signal initiation is
ubiquitous in B cells, yet the corresponding general mechanisms by which clustering is sensed and controlled
by intracellular components are unknown. A mechanistic understanding of clustering-mediated B cell signaling
events is essential because they play important roles in immune function, defects lead to diseases such as
cancer and immunodeficiency, and widely used immunotherapeutic drugs exploit these mechanisms. The goal
of this work is to develop a framework that describes how receptor organization is tied to receptor functions for
the class of B cell surface receptors that partition with ordered membrane domains. The working hypothesis is
that ordered domain stabilization provides a fundamental paradigm for the initiation and regulation of diverse B
cell signaling responses. The proposed research is guided by a predictive model of B cell receptor (BCR)
signaling developed in the previous funding cycle and experimentally tests predictions of this model extended
beyond BCR signaling alone. Guided by extensive preliminary data, three specific aims will be pursued: 1)
Establish a generalized mechanism of signaling activated by clustering B cell surface proteins, 2) Modulate B
cell membrane organization and signaling through optogenetic control of scaffolding elements, and 3) Identify
immunomodulatory roles facilitated by membrane domains in BCR signaling. The first aim will establish a general
sensing mechanism that describes signals initiated via clustering of more than 15 distinct B cell surface proteins
that are reported in the literature to partition with ordered domains. The second aim will define how scaffolding
elements template functional membrane organization that spans plasma membrane leaflets and the contribution
of this effect to ligand-independent signaling. The third aim will identify and isolate the roles that phase-like
membrane domains play in downstream cellular decision-making by modulating signals initiated through the
BCR. All aims use quantitative super-resolution fluorescence localization microscopy techniques with the
sensitivity to detect subtle domain-mediated interactions in chemically fixed and live cells. The proposed work is
innovative because it applies predictive models of membrane organization and exploits recent advances in
super-resolution imaging, biosensor technology, and optogenetics. A broadly applicable mechanistic model for
B cell signaling will drive future advances in basic B cell biology, elucidate the mechanisms underlying the
efficacy of several widely used B cell-targeted drugs, and provide new approaches for the treatment of immune
diseases.

## Key facts

- **NIH application ID:** 10183265
- **Project number:** 5R01GM110052-08
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sarah L Veatch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $292,046
- **Award type:** 5
- **Project period:** 2014-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183265

## Citation

> US National Institutes of Health, RePORTER application 10183265, Functional roles of lipid domains in B cell signaling (5R01GM110052-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10183265. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*