# Role of endothelial JAK/STAT signaling in the regulation of vascular leakage

> **NIH NIH R01** · ALBANY MEDICAL COLLEGE · 2020 · $364,500

## Abstract

Sustained vascular leakage due to prolonged or exacerbated inflammation leads to organ damage, lasting
sequelae and increased mortality. The mechanisms that mediate long-term loss of endothelial barrier function
are poorly understood. We propose that transcriptional changes in the endothelium, and in particular STAT3-
dependent gene regulation, may explain these long-term changes. STAT3 can promote opposing effects on
the endothelium. While inhibition of its phosphorylation (mediated by JAK kinases) is anti-inflammatory and
reduces endothelial permeability, endothelial STAT3 knockout actually increases vascular leakage. The
central hypothesis of this grant is that prolonged STAT3 phosphorylation promotes a pro-inflammatory
STAT3 transcriptional response that involves changes in the glycocalyx, including degradation of
hyaluronic acid, and drastic alterations in the actin cytoskeleton. This hypothesis challenges the current
understanding of the role of STAT3 in the endothelial inflammatory response by linking cytokine signaling to
sustained vascular leakage via a novel mechanism. A better understanding of this pathway not only can
explain multiple clinical observations, but also is expected to have a significant positive impact on future anti-
inflammatory treatments by identifying novel pharmacological targets to prevent and/or revert the systemic
vascular leakage without affecting other arms of the immune response that may be required for pathogen
clearing or tissue healing. We will combine in vitro and in vivo experimentation in the three separate aims to:
Identify the specific role of STAT3-dependent transcriptional mediators in endothelial barrier loss. We identified
novel STAT3-dependent genes downstream of IL-6, including endothelial glycocalyx catabolic enzymes and
modulators of the actin cytoskeleton. Loss of hyaluronan and actin stress fibers temporally correlate with IL-6-
induced loss of barrier function in HUVEC. We will determine any causal roles for these candidate genes.
Determine the requirement of endothelial STAT3 phosphorylation in promoting barrier function loss in vivo.
Phosphorylated and non-phosphorylated STAT3 may have different and even opposing roles. We will use
established models of sepsis to assess mice survival, vascular leakage and endothelial glycocalyx and
cytoskeletal regulation of STAT3 (STAT3iEKO) and gp130iEKO knockout mice, as well as mice harboring an
inducible, endothelial-specific knockin Y705F mutation (STAT3iE-Y705F).
Determine the role of feedback loops leading to STAT3 sustained activation in barrier function. We will
determine how an IL-6-induced sustained activation of STAT3 can lead to prolonged vascular leakage by
interfering with negative feedback loops involving SOCS3 and TC45. We will identify potential post-
translational modifications of the negative regulator SOCS3 that could lead to sustained STAT3 activation. To
assess the role of these loops in vivo, we will create endothelial-specific SOC...

## Key facts

- **NIH application ID:** 9985922
- **Project number:** 5R01GM124133-03
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** Alejandro Pablo Adam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985922

## Citation

> US National Institutes of Health, RePORTER application 9985922, Role of endothelial JAK/STAT signaling in the regulation of vascular leakage (5R01GM124133-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985922. Licensed CC0.

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