# TACE and Clock mechanisms in aging and vascular stiffening

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $448,702

## Abstract

PROJECT SUMMARY
Cardiovascular disease remains one of the leading causes of death in the world. Its progression is part of the
aging process. From mouse to man, one consistent feature of aging and cardiovascular disease is the stiffening
of blood vessels. This elastic property is tantamount to blood vessels to effectively deliver blood to target organs.
With progressive stiffening, the consequence can be organ failure and death often as a consequence of heart
attacks and strokes, which exhibit a unique timing, a circadian rhythm. Indeed, the molecular components of
circadian rhythm—the circadian clock, including Bmal1, Clock, Per, and Cry, which we have shown are
expressed and oscillating in blood vessels are intimately connected with the aging of blood vessels. In mice
with circadian dysfunction (Bmal1-KO mice), we have discovered that there is increased vascular stiffness in
their blood vessels, suggesting that a broken clock may speed the aging of blood vessels, and age-dependent
worsening of pathological vascular remodeling. We have also found that the disintegrin/metalloprotease
ADAM17/TACE tracks uniquely with age in human blood vessels, and that it exhibits a circadian rhythm as do
its outputs including JAM-1/F11r, TNF, and IL6r. Moreover, we also demonstrate that Bmal1-KO mice exhibit
increased levels of the cytokine outputs TNF and IL6, and in a microarray study find Bmal1-KO naïve and
transplanted vessels exhibit significant changes in ADAM17 targets. The central hypothesis of this application
is that dysfunction of circadian clock is a prime mediator of age-related impairment of arterial relaxation and
elasticity, which we propose is through ADAM17 regulation. Three Specific Aims are proposed. In Specific Aim
1 we will determine if a dysfunctional circadian clock mediates accelerated vascular dysfunction and arterial
stiffening in aging. In Specific Aim 2, we will dissect the arterial wall-intrinsic and extrinsic mechanisms, which
alter vascular clock and cause arterial stiffness in aging. In Specific Aim 3, we propose to examine the
relationship between circadian clock dysfunction and ADAM17 activation in age-dependent vascular stiffening.

## Key facts

- **NIH application ID:** 10180812
- **Project number:** 5R01AG054651-05
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Zsolt Bagi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $448,702
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180812

## Citation

> US National Institutes of Health, RePORTER application 10180812, TACE and Clock mechanisms in aging and vascular stiffening (5R01AG054651-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10180812. Licensed CC0.

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