Nuclear Receptor REV-ERBα as a Novel Modulator of Cadmium-Induced Chronic Airway Disease

Nuclear Receptor REV-ERBα as a Novel Modulator of Cadmium-Induced Chronic Airway Disease Cadmium (Cd) is a highly toxic environmental pollutant derived from natural sources such as volcanoes and wildfires, as well as anthropogenic activities including metalworking, coal-fired power plants, and military operations. Elevated levels of Cd have been found in the lungs of U.S. military personnel deployed to Iraq and Afghanistan, where it has been implicated in constrictive bronchiolitis and other serious lung disorders. Chronic occupational exposure to Cd, through activities like welding, grinding, and heating metals, can severely impair lung function and increase the risk of chronic airway diseases. Emerging evidence suggests that disruption of the circadian clock contributes significantly to the pathogenesis of chronic lung diseases. The circadian clock plays a vital role in regulating several important processes, including antioxidant defense mechanisms, epithelial- mesenchymal transition (EMT), and fibroblast-to-myofibroblast transition (FMT). These processes are essential for proper lung development, regeneration, and repair. Disruptions to the circadian rhythm can significantly impact lung health and the response to injury or environmental pollutants. The nuclear receptor REV-ERBα (encoded by NR1D1), a key circadian clock transcription factor, has been implicated in modulating FMT signaling and pulmonary fibrosis. Prior studies also indicate cell type-specific roles for circadian genes in alveolar type II (AT2) cells and lung fibroblasts in chronic lung disease progression. Preliminary data from our lab using a repeated Cd exposure model show impaired lung function, enhanced lung inflammation, and increased collagen deposition, accompanied by significantly reduced Rev-erbα expression. These changes are associated with the upregulation of pro-inflammatory and profibrotic genes and the downregulation of circadian clock genes. Myofibroblast-specific deletion of Rev-erbα leads to worsened lung function following Cd-induced lung injury. Despite these findings, the molecular mechanisms by which REV-ERBα modulates cadmium-induced chronic airway disease remain poorly understood. We hypothesize that Rev-erbα plays a critical, cell-type-specific role in regulating cadmium-induced persistent inflammation, lung function decline, circadian clock disruption, and fibrotic airway remodeling. Aim 1: Define the cell type-specific role of Rev-erbα in cadmium- induced persistent inflammation, fibrogenesis, and chronic airway disease using conditional knockout (cKO) mouse models. Aim 2: Determine whether pharmacological activation (Rev-erbα agonist SR29065) or genetic reconstitution (AAV9-Rev-erbα overexpression) can reverse cadmium-induced chronic airway disease phenotypes. Understanding how REV-ERBα modulates persistent inflammation and fibrogenesis in Cd-exposed lungs will provide novel insights into circadian clock-targeted therapies for environmentally induced chronic lung diseases. Project Number: 1R21ES038641-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Isaac Kirubakaran Sundar | Institution: UNIVERSITY OF KANSAS MEDICAL CENTER, KANSAS CITY, KS | Award Amount: $426,250 | Activity Code: R21 | Study Section: Environmental Determinants of Disease Study Section [EDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354925