# Defining the role(s) of CGRPα during cutaneous antifungal immunity

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $53,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Invasive Candidiasis (IC) is a life-threatening fungal infection that occurs when Candida spp. invade into deep
tissues and circulation. In patients with an intact immune system, Candida infections are self-limiting. However,
IC presents a serious threat to hospitalized and immunocompromised patients, resulting in ~350,000 deaths
globally each year. The growth of these vulnerable populations and emergence of treatment-resistant Candida
spp. have resulted in an urgent need for novel therapies to improve patient mortality. Recently, it has been
appreciated that nociceptors (pain-sensing neurons) and the neuropeptide Calcitonin gene-related peptide alpha
(CGRP) potentiate antifungal immunity in the skin by a mechanism yet to be defined. Therefore, an improved
mechanistic understanding of CGRP may expand the prophylactic and therapeutic armamentarium for IC.
Based on our preliminary studies, we hypothesize that CGRP is released by nociceptors in the skin and directly
acts on local Dendritic Cells (DC) to induce IL-23 production and Type-17 inflammation. Here we propose 2
specific aims to directly test our hypothesis and characterize the cell-specific direct and secondary effects of
CGRP on antifungal immunity. Aim 1: Determine the obligate source(s) and target(s) of CGRP required
for robust antifungal immunity using a Candida albicans infection model. Subaim 1A: We will ablate
CGRP in cutaneous nociceptors in order to test the requirement of nociceptor-derived CGRP for robust
antifungal Type-17 immunity. Subaim 1B: We will ablate the CGRP-specific receptor subunit (RAMP1) in DCs
in order to test the requirement of CGRP acting on DCs for robust antifungal Type-17 immunity. Through these
subaims we will delineate a cellular circuit responsible for CGRP-mediated antifungal immunity. Aim 2: Test
the functional requirement of CGRP signaling for cellular and transcriptional responses during a C.
albicans infection model by two complementary subaims of single-cell transcriptomics. Subaim 2A: We
will generate chimeric mice reconstituted with congenically distinct RAMP1KO and WT bone marrow progenitors
and perform single-cell RNA-sequencing (scRNA-seq) on immune cells isolated from infected skin. By differential
analyses of RAMP1KO and WT effector populations from the same infection, we will isolate transcriptional
programs downstream of CGRP/RAMP1 signaling. Subaim 2B: We will perform spatial multi-omics analyses
on infected skin from CGRP receptor antagonist- and vehicle-treated mice to test the requirement of
CGRP/RAMP1 signaling for downstream transcriptional, cellular and microenvironment phenotypic changes
during antifungal immunity. We will use single-cell transcriptomics with spatial context to define transcriptional
signatures in situ and cell-cell interactions/communities that depend on CGRP/RAMP1 signaling. Through
these subaims we will characterize the direct and secondary effects of CGRP during antifungal ...

## Key facts

- **NIH application ID:** 10996336
- **Project number:** 1F30AI181455-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jacob Gillis
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996336

## Citation

> US National Institutes of Health, RePORTER application 10996336, Defining the role(s) of CGRPα during cutaneous antifungal immunity (1F30AI181455-01A1). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10996336. Licensed CC0.

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