# Nitric oxide-mediated changes in glymphatic and CSF systems in aging and Alzheimer's disease

> **NIH NIH RF1** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $463,521

## Abstract

ABSTRACT
SARS-CoV-2 contact with the organism starts with binding to its key receptor ACE2 which is highly
expressed in the ciliated cells of the tracheal, bronchial, and nasal mucociliary epithelium. After binding,
the virus inhibits the cilia beating in the airways and suppresses mucociliary transport, the first line of
defense against invading microorganisms. Thus, augmenting the ciliary function may prevent the viral
infection at the very first steps or help fight the further propagation of the virus. ACE2 is also expressed
in selected brain cells, underlying the neurological effects of SARS-CoV-2.
The main objective of this supplement is to rapidly build a screening system, to identify drugs that can
be immediately applied for COVID-19 therapy, and to use the gained knowledge for expanding the
screen to a broader range of candidate compounds.
In our NIA supported grant we discovered the critical role of the nNOS-NO-cGC-cGMP signaling
pathway for ciliary activity in the brain and the airways. Here we describe our plans of targeting this
pathway with clinically-approved drugs in order to augment cilia activity and airways clearance. This
project can be later extended to build a sensitive and powerful drug screen for anti-COVID-19 therapy.
In our first Specific Aim we will develop a comprehensive computational toolbox and use it to
determine the key parameters (a signature) of the cilia activity in the airways’ and brain ciliated cells
from humans and humanized mouse model. In the second Specific Aim, we will apply our setup to
determine the signature of the cilia response to S1, the main cell binding ligand of SARS-CoV-2, and to
S1-expressing pseudotyped VSV-S1 virus. Finally, in our third Specific Aim we will examine anti-
SARS-CoV-2 drugs currently used in clinic and clinically-approved compounds that activate the NO-
cGMP pathway, as well as their combination to determine if such treatments can rescue the S1-affected
cilia activity in the airways and brain preparations. In the same set of experiments we will examine the
response of preparations from animals of different age, which may contribute to the profound old age-
bias of COVID-19. We emphasize that our selection of drugs to be tested is limited to the
therapeutically-approved compounds, thus enabling rapid translation of our findings into clinical
practice.

## Key facts

- **NIH application ID:** 10177549
- **Project number:** 3RF1AG057705-01S1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Helene D Benveniste
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,521
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177549

## Citation

> US National Institutes of Health, RePORTER application 10177549, Nitric oxide-mediated changes in glymphatic and CSF systems in aging and Alzheimer's disease (3RF1AG057705-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177549. Licensed CC0.

---

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