# Project-003

> **NIH NIH U19** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $445,000

## Abstract

PROJECT SUMMARY
Patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and 
remodeling refractory to corticosteroid treatment. In this Project 3 (Vijayanand, PI), we propose to investigate 
how airway remodeling events in severe asthma are driven by this poorly characterized CD4+ T cell subset –
cytotoxic/pro-inflammatory CD4+ TRM cells. In the context of lung cancer and viral infections, our laboratory has 
recently shown the importance of both TRM cells and cytotoxic CD4+T cells in immune responses. In collaboration 
with Drs. Broide and Croft, Project 1 and 2, we are fully geared to explore the role of this novel cytotoxic TRM
subset in driving airway remodeling. Our long-standing collaboration with the University of Southampton, UK, 
will enable continued access to airway specimens from patients with severe asthma enrolled in the WATCH 
study (Southampton, UK) that currently consists of >500 subjects (Asthma Clinical Core B). In Aim 1, we will 
define the functional role of cytotoxic CD4+ TRM cells in driving airway remodeling using in vitro cell culture models 
of asthmatic airway structural cells. We will first determine the molecules expressed and released by 
cytotoxic/pro-inflammatory CD4+ TRM cells; then, we will test if products released by cytotoxic CD4+ TRM cells 
induce remodeling features in airway structural cells. We will individually test the activity of molecules released 
by cytotoxic TRM cells, such as TNF, LIGHT, to narrow down targets that are significant drivers of remodeling 
events. We will also determine if cytotoxic TRM cells can cause pyroptosis and/or necroptosis, i.e., inflammatory 
cell death of airway structural cells, which can, in turn, promote remodeling. In Aim 2, we will perform unbiased 
enhancer profiling studies in cytotoxic CD4+ TRM cells to define transcription factors that play an important role in 
the differentiation and function of these cells. Then, we will knock down candidate transcription factors identified 
in T cells and determine their effects on the differentiation and function of cytotoxic TRM cells in vitro. Overall, 
studies in this program will improve our understanding of how cytotoxic CD4+ TRM cells are generated and how 
they interact with airway structural cells to drive remodeling events in severe asthma.

## Key facts

- **NIH application ID:** 10869419
- **Project number:** 5U19AI070535-18
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** DAVID H BROIDE
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $445,000
- **Award type:** 5
- **Project period:** 2006-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869419

## Citation

> US National Institutes of Health, RePORTER application 10869419, Project-003 (5U19AI070535-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10869419. Licensed CC0.

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