# Endothelial Cell-Intrinsic Non-Canonical NF-kB in Chronic inflammation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $389,620

## Abstract

SUMMARY
Chronic inflammation is associated with autoimmune diseases, including rheumatoid arthritis, and is
responsible for high morbidity and mortality rates in western society. Consequently, developing effective
strategies to prevent or inhibit inflammation is a highly significant objective that will profoundly impact human
health care. Activation of vascular endothelial cells (EC) plays a crucial role in the pathology of chronic
inflammatory diseases. Our long-term research goal is to identify the specific intracellular signals that underlie
EC activation, as this will reveal targets for novel therapeutic strategies aimed at preventing or treating chronic
inflammation. A major signaling mechanism associated with inflammation is activation of the NF-κB family of
transcription factors. Two independent mechanisms of NF-κB signaling named the classical and non-canonical
pathways have been described and each regulates discrete functions. For example, extensive studies have
established key roles for classical NF-κB signaling in the pro-inflammatory function of EC and we recently
defined a major function for EC-intrinsic classical NF-κB in arthritis. However, emerging evidence strongly
supports a role for the non-canonical pathway during the development of chronic inflammation. Our published
work and preliminary data has demonstrated that ligation of the lymphotoxin-β receptor (LTβR) activates the
non-canonical NF-κB pathway in EC and upregulates expression of crucial pro-inflammatory and pro-
angiogenic genes. To date however, no genetic models exist to directly study non-canonical NF-κB signaling in
EC in vivo and there are no pharmacological approaches available to specifically target the non-canonical
pathway. To address these significant roadblocks, we have developed a new in vivo mouse model
conditionally lacking non-canonical NF-κB signaling in EC. In addition, we pioneered an innovative
pharmacological approach to selectively target pathway-specific inhibitory polypeptides to activated EC in vivo.
The goal of this proposal is to determine the precise function of non-canonical NF-κB signaling in EC and to
test our overarching hypothesis that “non-canonical NF-κB signaling regulates the pro-inflammatory function of
endothelial cells”. Accordingly, we will pursue the following three specific aims: (1) To determine how
endothelial cell-intrinsic non-canonical NF-κB signaling controls angiogenesis; (2) To define the role of
endothelial cell-intrinsic non-canonical NF-κB signaling in arthritis; (3) To selectively pharmacologically inhibit
non-canonical NF-κB activation in endothelial cells. These studies will for the first time directly address the
effects of selectively abrogating non-canonical NF-κB signaling in EC on the pro-inflammatory function of this
critical cell type. Accomplishing our aims will provide novel insight into the potential therapeutic value of
targeting non-canonical NF-κB signaling in arthritis and other chronic inflammatory ...

## Key facts

- **NIH application ID:** 9918246
- **Project number:** 5R01AR066567-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MICHAEL J MAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,620
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918246

## Citation

> US National Institutes of Health, RePORTER application 9918246, Endothelial Cell-Intrinsic Non-Canonical NF-kB in Chronic inflammation (5R01AR066567-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9918246. Licensed CC0.

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