# How inflammation and thrombosis fuel disease and aging: Focus on NETs

> **NIH NIH R35** · BOSTON CHILDREN'S HOSPITAL · 2021 · $885,000

## Abstract

How inflammation and thrombosis fuel disease and aging: Focus on NETs
This R35 0IA application is an extension based on two recently funded NHLBI RO1
grants entitled “NETS in thrombosis and inflammatory responses” and “NETs and their
modulating enzymes in age-related inflammatory diseases.” For many years, we have
conducted a successful research program studying thrombosis and inflammation. Our
current emphasis is on newly discovered neutrophil extracellular traps (NETs). Upon
neutrophil activation, peptidylarginine deiminase 4 (PAD4) translocates to the nucleus
to citrullinate histones. This decondenses chromatin, which is released as NETs. NETs
trap microbes but we have shown a dark side of NETs, i.e., they promote thrombosis,
inflammation and age-related heart and lung fibrosis. The central hypotheses of our
program are: NETs are involved in the formation of a stable organized and
vascularized thrombus and breaking up NETs is necessary for thrombolysis.
Thrombosis promotes deposition of NETs in the adjacent vessel wall and also in
distant organs leading to post-thrombotic syndrome and an increased systemic
pro-coagulant and pro-inflammatory state. Aging promotes NET formation and
NETs in turn escalate chronic inflammatory and thrombotic diseases. We believe
that inhibition of the process of NET formation or destruction of NETs would be
beneficial to the host. Finally, we hypothesize that genes regulating NETosis, such
as peptidylarginine deiminase 4 (PAD4), impact aging.
The work by the “Wagner Lab” is considered innovative and solid; an objective measure
is its high citation. The lab has always been funded by more than one NHLBI grant and
for 15 years I was also the PI of a large PPG in Transfusion Biology. However, in the
recent difficult funding period too much of my time was spent on securing support for my
group. Obtaining prolonged funding would free my time for more mentoring, writing
reviews, and collegiate activities. In addition, we now study chronic inflammatory
diseases and their impact on aging. These experiments take time and the extended
duration of support would assure that we could pursue this exiting research effectively.

## Key facts

- **NIH application ID:** 10086105
- **Project number:** 5R35HL135765-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** DENISA D WAGNER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $885,000
- **Award type:** 5
- **Project period:** 2017-01-11 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086105

## Citation

> US National Institutes of Health, RePORTER application 10086105, How inflammation and thrombosis fuel disease and aging: Focus on NETs (5R35HL135765-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086105. Licensed CC0.

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