# Stress Signaling Pathways Linking Endothelial Injury to Graft Arteriosclerosis

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

STRESS SIGNALING PATHWAYS LINKING ENDOTHELIAL INJURY TO GRAFT ARTERIOSCLEROSIS
Abstract:
The overall hypothesis of this application is that graft arteriosclerosis (GA), the major cause of late cardiac
allograft failure, results from a chronic host T cell response to allogeneic graft endothelial cells (ECs) that takes
the form of delayed-type hypersensitivity DTH within the vessel wall, locally generating IFN- which is
responsible for driving vascular smooth muscle cell (VSMC) proliferation and intimal hyperplasia. The clinical
correlations and evidence from other experimental systems have suggested that non-immune factors,
especially peri-operative stress-induced alterations in the graft, are important contributors to GA pathogenesis.
It is proposed and demonstrated experimentally that signals in the graft, primarily from ECs, generated as a
result of peri-operative stress can produce mediators that influence T cell activation and differentiation.
However, how the peri-operative stresses such as hypoxia couple intracellular signaling pathway to alter ECs
alloimmunity and GA is not understood. We have identified SENP1 is a critical mediator of peri-operative
stresses. We hypothesize that SENP1 mediates the responses to non-immune peri-operative injuries of graft
ECs, increasing T cell-mediated alloimmunity and GA. We propose to explore this hypothesis in the following
specific aims: 1) Characterize SENP1-enhanced cytosolic NOX2 activity that mediates peri-operative stress-
induced EC immunogenicity and GA progression. We will elucidate the mechanisms by which SENP1
activates NOX2-dependent ROS generation in ECs, define the role of SENP1-NOX2 axis in peri-operative
stress-exacerbated GA progression in vivo using EC-specific SENP1 knockout mice and NOX2-deficient as
graft donors, and determine how SENP1 couples NOX2 deSUMOylation to EC phenotypic changes. 2)
Characterize SENP1-mediated deSUMOylation and disruption of mitochondrial Trx2 activity that augments
peri-operative stress-induced EC immunogenicity and GA progression. We will elucidate the mechanisms by
which SENP1 attenuates Trx2-dependent mitochondrial function in EC, define the role of mitochondrial
SENP1-Trx2 axis in peri-operative stress-exacerbated GA progression in vivo using EC-specific Trx2-
transgenic mice expressing WT, SUMO-defective KR mutant and Trx2-SUMO fusion forms as graft donors,
and determine how SENP1 couples Trx2 deSUMOylation, mitochondrial dysfunction and ROS production to
EC phenotypic changes that modulate T cell responses. 3) Characterize SENP1-ROS-ASK1 signaling
pathway that mediates peri-operative stress-induced EC immunogenicity and GA progression. We will
determine if cytosolic SENP1-NOX2 and mitochondrial SENP1-Trx2 converge on ASK1 in regulating EC
function and GA progression, determine how SENP1-NOX2 and SENP1-Trx2 couple ASK1 to EC phenotypic
changes that modulate T cell responses, and test if pharmacological inhibitors of SENP1, NOX2, TRX2 and
SENP1 could ...

## Key facts

- **NIH application ID:** 9850093
- **Project number:** 5R01HL109420-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JORDAN S POBER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2012-04-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850093

## Citation

> US National Institutes of Health, RePORTER application 9850093, Stress Signaling Pathways Linking Endothelial Injury to Graft Arteriosclerosis (5R01HL109420-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9850093. Licensed CC0.

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