# TPSAB1-derived tryptases promote myeloproliferation and anaphylaxis

> **NIH NIH R00** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $788,420

## Abstract

PROJECT SUMMARY/ABSTRACT:
A critical need exists to identify factors which place sensitized individuals at risk for anaphylaxis in order to
devise targeted therapies to limit reaction severity. In the absence of the proposed work, allergic individuals –
frequently children – will be at continuously increasing risk for anaphylaxis with potentially fatal consequences.
Recently the Principle Investigator (PI) identified increased TPSAB1 copy number as the common cause of
elevated basal serum tryptase (BST), a well-established risk factor for severe anaphylaxis. The long-term goal
of this project is to develop therapies targeting the symptoms associated with increased TPSAB1 expression,
including anaphylaxis, in humans. The principle objective of this proposal is to determine how increased
TPSAB1 expression in myeloid cells alters their reciprocal relationship with neighboring cells to promote
severe allergic reactions. Based upon clinical observations and published reports, the central hypothesis for
this proposal is that elevated BST due to increased TPSAB1-derived tryptase expression promotes
myeloproliferation and anaphylaxis in humans. Our rationale is that through identification of the mechanism(s)
leading to TPSAB1 over-expression and by defining the activities of these tryptases in vivo, new therapeutic
strategies will be developed to prevent anaphylaxis and target myeloid dyscrasias. To test our central
hypothesis, we propose three specific aims to: (1) elucidate mechanisms by which specific tryptase expression
patterns promote severe allergic reactions; (2) identify pathways governing TPSAB1 gene expression and
associated myeloid proliferation; (3) define additional pathways essential to severe allergic reactions by
identifying novel genetic mutations leading to elevated BST and anaphylaxis. This project is significant
because it will establish mechanisms by which elevated BST and associated myeloproliferation can promote
severe allergic reactions and anaphylaxis, and identify targets for therapeutic intervention. This project is
based upon our identification of the role that TPSAB1 copy number variation and gene expression play in BST
levels. This major conceptual advance was enabled by state-of-the-art genotyping and gene expression
assays developed by the PI. In this project, these tools will be applied in an innovate manner: 1) to devise a
non-invasive strategy to identify patients in whom clonal myeloid disease is highly probable; and 2) to dissect
the relationship(s) between tryptase isoform expression, elevated BST, anaphylaxis, and clonal myeloid
disease. Furthermore, the central hypothesis will be tested in an innovative system, employing a humanized /
bone marrow xenotransplantation mouse model that optimizes myeloid engraftment, not previously used to
study anaphylaxis. The proposed studies will provide important insights into the pathways governing severe
allergic reactions in humans, and bridge the disparate fields of allergy a...

## Key facts

- **NIH application ID:** 11011627
- **Project number:** 4R00AI138586-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jonathan Lyons
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $788,420
- **Award type:** 4N
- **Project period:** 2018-07-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11011627

## Citation

> US National Institutes of Health, RePORTER application 11011627, TPSAB1-derived tryptases promote myeloproliferation and anaphylaxis (4R00AI138586-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11011627. Licensed CC0.

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