# The NOTCH Signaling Pathway in Large Vessel Vasculitis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $569,098

## Abstract

Project Summary
Giant Cell Arteritis (GCA) is an autoimmune and autoinflammatory disease which targets the aorta and its major
branch vessels. GCA causes vaso-occlusive disease, leading to blindness and stroke. About half of the patients
develop GCA aortitis, a potentially life-threatening complication due to aortic dissection and aneurysm formation.
The underlying disease process is a granulomatous arteritis, with CD4 T cells, macrophages and multinucleated
giant cells infiltrating into the vessel wall, eliciting maladaptive wall remodeling with neoangiogenesis and lumen-
occlusive intimal hyperplasia.
We have identified aberrant expression of the oncogene NOTCH1 in CD4 T cells as a key abnormality in the
immune system of GCA patients. Here, we will examine the hypothesis that NOTCH signaling transforms
protective immunity into pathogenic immunity by suppressing the mitochondrial enzyme succinate
dehydrogenase (SDH) and truncating the tricarboxylic acid (TCA) cycle. Fragmentation of the TCA cycle
then leads to the accumulation of the metabolic intermediate succinate, which is released into the tissue
site and functions as a second messenger. We propose that succinate secreted by NOTCH1hi SDHlo CD4
T cells targets surrounding cells to redirect T effector cell differentiation, to induce multinucleated
macrophages and to promote microvascular neoangiogenesis. We have assembled key enabling resources
to mechanistically study how NOTCH-instructed succinate release enhances vascular inflammation; including a
large cohort of clinically well phenotyped GCA patients and a chimeric mouse model in which vasculitis is induced
in engrafted human arteries to corroborate in vitro data by in vivo studies. Aim 1 will define the molecular
mechanisms leading to NOTCH-dependent SDH loss-of-function, building on preliminary studies that implicate
RNA-binding proteins in regulating SDH mRNA stability through N6-methyladenosine modifications. Aim 2A
examines mechanistically how succinate reprograms T effector cell differentiation. Experiments are designed to
investigate how succinate paralyzes the NF-kappaB inhibitor A20/TNFAIP3 to unleash NF-kappaB signaling and
induce polyfunctional effector T cells (Thpoly), including T cells that co-produce IFN-, IL-17, TNF-α, IL-21 and
IL-22. Aim 2B will determine how NOTCH-instructed succinate alters macrophage function, specifically by
driving formation of tissue-destructive multinucleated giant cells. We will delineate how succinate elicits a robust
DNA damage response and how it promotes nuclear division and halts cytokinesis by interfering with the spindle
assembly checkpoint. Aim 2C is focused on succinate’s role in inducing a pro-angiogenic endothelial cell (EC)
phenotype and will explore how succinate-trained EC migrate, proliferate, and lose their barrier function. Aim 3
will bridge from the bench to the bedside and will test whether the suppression of succinate production by
blocking the upstream enzyme a-ketoglutarate...

## Key facts

- **NIH application ID:** 10316892
- **Project number:** 2R01HL117913-06A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Cornelia M. Weyand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $569,098
- **Award type:** 2
- **Project period:** 2014-01-06 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316892

## Citation

> US National Institutes of Health, RePORTER application 10316892, The NOTCH Signaling Pathway in Large Vessel Vasculitis (2R01HL117913-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10316892. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*