# Restoring mucociliary clearance apparatus to mitigate lung inflammation in the context of HIV and cigarette smoke

> **NIH NIH R03** · FLORIDA INTERNATIONAL UNIVERSITY · 2022 · $147,500

## Abstract

PROJECT SUMMARY
People living with HIV demonstrate increased incidence of lung inflammation and HIV is an independent risk
factor development of COPD. HIV Tat, an immediate early protein of HIV and cigarette smoke suppress the
deacetylase SIRT1 that regulates ADAM17, a protease involved in activating Notch signaling as well as
proteolytic cleavage and activation of proinflammatory cytokines. This can lead to downstream deleterious
effects on ciliogenesis, mucociliary clearance and lung function decline. While chronic inflammation in COPD is
a multifactorial etiology, impaired mucociliary clearance leading to recurrent lung infections can play an important
role in promoting lung inflammation. Optimal mucociliary clearance requires mucus, cilia, and a thin layer of
airway surface liquid to facilitate ciliary beating. Abnormalities in any compartment of the mucociliary system can
compromise mucus clearance leading to mucus impaction entrapping bacteria and promoting chronic bacterial
infection.
HIV Tat promotes an aberrant microRNAome in the primary bronchial epithelium and upregulates miR-142-5p,
a microRNA known to suppress SIRT1. This proposal will identify mechanisms involved in HIV Tat promotes
mucociliary dysfunction and identifying individual effects on ciliogenesis, mucus hypersecretion and
inflammation. Given the causal role for SIRT1 suppression in mediating these effects, we will use a novel
CRISPR-mediated gene specific microRNA antagonism approach to disrupt the miR-142-5p target site on the
SIRT1 3’UTR. This will preserve SIRT1 expression in the context of HIV Tat and cigarette smoke without affecting
other functions of miR-142-5p. Aim 1: HIV Tat upregulates miR-142-5p and suppress SIRT1 exacerbate
upregulates ADAM17 levels by HIV and cigarette smoke exposure in NHBE ALI cultures. Given that HIV Tat and
cigarette smoke mediated miR-142-5p dysregulation leading to SIRT1 suppression and aberrant Notch signaling.
Specifically, we will analyze ADAM17 upregulation, ciliogenesis, goblet cell hyperplasia and ciliary beat
frequency in NHBE ALI cultures. Aim 2: Since HIV Tat and cigarette smoke suppresses SIRT1, and SIRT1
suppression impairs mucociliary clearance apparatus, we will determine if gene-specific microRNA antagonism
in combination with SIRT1 activator to rescue SIRT1 levels, suppression of inflammation and enhance
mucociliary clearance apparatus in primary bronchial epithelial cells treated with HIV Tat and exposed to
cigarette smoke.

## Key facts

- **NIH application ID:** 10547928
- **Project number:** 1R03DA057162-01
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Srinivasan Chinnapaiyan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $147,500
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547928

## Citation

> US National Institutes of Health, RePORTER application 10547928, Restoring mucociliary clearance apparatus to mitigate lung inflammation in the context of HIV and cigarette smoke (1R03DA057162-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10547928. Licensed CC0.

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