# A SYSTEMS BIOLOGY APPROACH TO IDENTIFYING THE MECHANISMS OF SEX HORMONE INDUCED THROMBOEMBOLISM IN PRE-MENOPAUSAL WOMEN

> **NIH NIH R33** · UNIVERSITY OF COLORADO DENVER · 2020 · $646,004

## Abstract

Hormone therapies like oral contraception (OC) confer a heightened risk of venous thromboembolism (VTE) in
premenopausal women. Until we gain mechanistic insights into why this happens, it is not possible to predict
who is at risk for sex hormone-induced VTE. The long-term goal of this research is to identify the mechanisms
by which sex hormones modulate hemostasis and thrombosis. The overall objective in this application is to
determine how OC alter platelet function using a systems biology approach that combines –omics technologies
with computational models. Previous work on hormone-induced VTE have implicated several mechanisms
related to platelet function including response to agonists, metabolism of arachidonic acid (AA), and gene
expression. Systematic studies of these processes over different time scales and how they relate to each other
is lacking and will be addressed here. The central hypothesis is that OC increase platelet reactivity over three
time scales; (i) acutely (seconds-minutes) by potentiating calcium release from intracellular stores, (ii)
metabolically (minutes-hours) by elevating thromboxane metabolism, and (iii) genomically (days-months) by
altering the expression of adhesive receptors. This hypothesis is based on preliminary data that platelets
incubated with physiologic concentrations of 17β-estradiol have higher intracellular calcium concentrations
following adhesion to collagen and altered central metabolism. The rationale for the proposed research two-
fold: (i) the development of new tools to study hormone-induced VTE over multiple time scales, and (ii) to
measure the effects of exogenous hormones on platelet function over these time scales. This hypothesis will
be tested by two specific aims: 1) Development of systems biology tools. 2) Measuring the effects of OC on
platelet function over diverse time scales. Under the first aim, computational models of calcium dynamics and
metabolism in platelets will be developed informed by experiments of platelet adhesion and metabolic flux
analysis. Additionally, we will perform sequencing of gene variants known to affect platelet function and
hormone receptors. Finally, existing microfluidic models of vascular injury will be refined to incorporate
endothelial cells to measure platelet-endothelium interactions. Under the second aim, we will use the tools
developed in the first aim to measure changes in platelet function following acute and chronic exposure to
exogenous hormones. These studies will include tracking platelet function in a cohort of women prior to and
after starting OC. The approach is innovative because it represents a new and substantive departure from the
status quo by using a systems biology approach to measure and model the influence of sex hormones on
platelet function over time scales of seconds to years. The proposed research is significant, because it will
identify the mechanism(s) by which exogenous sex hormone confer a pro- and/or antiplatelet phenotype...

## Key facts

- **NIH application ID:** 10026348
- **Project number:** 4R33HL141794-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jorge A Di Paola
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $646,004
- **Award type:** 4N
- **Project period:** 2019-07-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026348

## Citation

> US National Institutes of Health, RePORTER application 10026348, A SYSTEMS BIOLOGY APPROACH TO IDENTIFYING THE MECHANISMS OF SEX HORMONE INDUCED THROMBOEMBOLISM IN PRE-MENOPAUSAL WOMEN (4R33HL141794-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026348. Licensed CC0.

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