# TACE and Clock mechanisms in aging and vascular stiffening

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $385,000

## Abstract

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, end organ
delivery of oxygen, nutrition, and molecular communication can lead to organ failure, dementia,
and/or death. This age-dependent vascular dysfunction can lead to acute events, like heart
attacks and strokes, which do exhibit a circadian rhythm in onset, but can also lead to progressive
decline in cognitive function, which are also linked to circadian rhythm. The circadian clock,
Bmal1, Clock, Per, and Cry, are expressed and oscillating in blood vessels and intimately
connected with the aging of blood vessels. In 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 TNF, IL6r,
and F11r. In aorta of young mice, we have now found that Alzheimer Disease blood marker
exhibits a circadian rhythm, a rhythm that is lost in old mice. 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, and as part of
a supplemental application, we will extend our proposal to determine if these signals from the
periphery can contribute to Alzheimer’s Disease pathology in mice. 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 will examine the mechanisms through which circadian
clock dysfunction leads to arterial aberrant ADAM17 signaling and vascular dysfunction in aging.

## Key facts

- **NIH application ID:** 10123645
- **Project number:** 3R01AG054651-04S1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Zsolt Bagi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 3
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123645

## Citation

> US National Institutes of Health, RePORTER application 10123645, TACE and Clock mechanisms in aging and vascular stiffening (3R01AG054651-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123645. Licensed CC0.

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