# Repurposing Pharmacological Agents for Inherited Mast CellDisorders of the Gut

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $258,460

## Abstract

Abstract
Mast cell (MC) disorders are heterogenous, have not been well characterized, and treatment
algorithms are still being developed. Recently, a new understanding of MC disease has
emerged, with allergy/atopy and with rare, neoplastic mastocytosis comprising MC activation
disease. The rest of the disorders are ill-defined, with complex heterogenous presentation of
MC activation syndrome that features chronic multisystem inflammation with or without the
atopic profile or aberrant growth of MC in various tissues. In this study, MC from patients with
hereditary alpha tryptasemia (HAT), a disorder where multiple copies of the TPSAB1 gene
correlate with elevated serum tryptase, are used to study the effect of MC phenotype and
function on the chronic inflammatory effects in the gut. This knowledge will be utilized to develop
new therapeutic uses for existing drugs that target MC functional pathways. The purpose of this
multicenter Clinical and Translational Sciences Institute (CTSI) supplement is to employ current
state-of-the-art techniques to elucidate differences in functional MC and inflammatory gut tissue
in patients with HAT compared with control tissues, and MC in patients with inflammatory bowel
disease (IBD, with and without remission), and in patients with systemic mastocytosis (SM).
Mass CyTOF, RNAseq, RNAscope and phosphorylation studies will be done on both MC from
lamina propria monocytic cells from right colon or ileum tissue and in gut tissue sections and
from differentiated peripheral blood mononuclear cell (PBMC)-derived progenitor CD34+ cells.
The results will reveal effects of these MC on the immune system and will target pathways for
treatment of generalized MC disorders by utilizing the Drug Repurposing Network (DRN) at the
University of New Mexico Center for Molecular Discovery, a high throughput flow cytometry-
based mechanism to screen 1,280 FDA-approved compounds per patient MC or PBMC. Our
hypothesis is that intestinal MC populations from HAT patients have an aberrant phenotype and
function, without clonal expansion of MC as in SM, that leads to a proinflammatory state in the
gut. We propose to link these HAT MC characteristics to endpoints that can be explored in the
DRN. Assays will be developed to target specific pathways important in MC regulation of
inflammation, for example to assay drugs targeting MGBPRX2, mTOR and JAK/STAT.
Proinflammatory cytokines TNF, IL-1b, IL-6 and IFN-g will be monitored to assess the effect of
high levels of tryptase on PBMC for the purposes of screening in the DRN. Through better
understanding of the phenotype and function of these HAT patient gut MC, we will be able to
identify personalized, mechanistic treatment algorithms that may be applicable to other MC
disorders.

## Key facts

- **NIH application ID:** 10319276
- **Project number:** 7R21TR002639-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SARAH C GLOVER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $258,460
- **Award type:** 7
- **Project period:** 2021-03-11 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319276

## Citation

> US National Institutes of Health, RePORTER application 10319276, Repurposing Pharmacological Agents for Inherited Mast CellDisorders of the Gut (7R21TR002639-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10319276. Licensed CC0.

---

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