# Mechanisms regulating the biosynthesis and signaling of oxylipins

> **NIH NIH R35** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $401,250

## Abstract

PROJECT SUMMARY
Oxylipins are oxygenated bioactive lipids derived from polyunsaturated fatty acids that have diverse and
integral functions in health and disease, including inflammation, cancer, and cardiovascular diseases. Oxylipins
are short-lived, locally acting signaling molecules that are synthesized on demand by cyclooxygenases (COX),
lipoxygenases (LOX), or cytochrome P450 monooxygenases. Advances in lipidomics have led to the detection
of disease-specific changes in oxylipins. Although the identification of disease-specific changes in oxylipins has
the power to be used for disease diagnosis, prognosis, or treatment, the translation of lipidomic studies into the
clinic remains challenging due to a lack of biological understanding of oxylipins. To better understand the
clinical relevance of disease-specific changes, we identified critical gaps in our knowledge that need to be
addressed, including 1) what mechanisms regulate the coordinated synthesis of multiple oxylipins leading to
cell-specific oxylipin patterns; and 2) how the signals elicited from individuals oxylipins are integrated into
biological functions. To address these gaps in our knowledge, the long-term goal of our research program is
to decipher the signaling mechanism responsible for the synthesis and function of individual oxylipins to
understand the functional consequence of their alterations in diseases. Without further mechanistic insights
into disease-specific changes in oxylipins, it is unlikely novel oxylipins will be effectively targeted for clinical
purposes. Platelets are the ideal model system to study oxylipin biology because they produce nanomolar
levels of approximately 15 oxylipins from COX and 12(S)-lipoxygenase (12-LOX) and offer a simplified model
to study the biological consequences of oxylipin dysregulation. In this proposal, we will focus on the function of
12-LOX and its arachidonic acid (AA)-derived metabolite, 12-HETE, which have broad clinical and biological
significance. However, due to the lack of consensus on the function of 12-HETE, the mechanism by which 12-
LOX contributes to inflammation, cancer progression, and clotting is controversial and represents a substantial
knowledge gap. This proposal will study 12-LOX and 12-HETE as a prototypical examples to address its role in
disease, and develop tools to characterize the function of oxylipins by using gene-edited human
megakaryocytes, which have been shown to faithfully recapitulate the donor-derived platelets. Our short-term
goals are to 1) determine the intracellular mechanisms used to release and deliver substrate to 12-LOX and 2)
identify the downstream signaling pathway(s) activated by 12-HETE in platelets. Our studies will provide
valuable insight into the mechanistic understanding of oxylipin synthesis and function that could ultimately aid
in developing new therapeutic approaches for a broad range of diseases.

## Key facts

- **NIH application ID:** 10890099
- **Project number:** 5R35GM150691-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Benjamin Eric Tourdot
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,250
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890099

## Citation

> US National Institutes of Health, RePORTER application 10890099, Mechanisms regulating the biosynthesis and signaling of oxylipins (5R35GM150691-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890099. Licensed CC0.

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