The vision of our research program is to determine how mitochondria orchestrate epithelial repair, cellular senescence and immune cell function in diseases of accelerated lung aging to identify new therapeutic approaches.
As a mentor and scientist, my goal is to bring value and meaningful scientific advances to our community by fostering the careers of young scientists, which requires a diverse, inclusive and creative next generation. Within my laboratory, I promote an environment that places unwavering value in teamwork, equity, inclusion and respect. As a laboratory, our philosophy and environment fosters creative and diverse thinking, provides agency and voice to each member with open communication and ensures professional career development at all levels of experience.
We are interested in identifying new molecular pathways connecting mitochondrial function with epithelial repair, cellular senescence and innate immune cell function in the pathogenesis of chronic obstructive lung disease (COPD) and pulmonary fibrosis to improve therapeutic options for patients. Our lab specifically studies the role of adenine nucleotide translocase (ANT, a canonical mitochondrial ADP/ATP transporter) in the lung epithelium and innate immune cells in the context of cigarette smoking-related lung disease and lung fibrosis. We want to better understand how, in health and disease, ANT regulates epithelial and macrophage function through mitochondrial metabolism and cellular senescence. We have also found that ANT plays a role in airway epithelial homeostasis through surface hydration and the action of tiny motile cilia in the airway. We utilize a repertoire of relevant murine models of injury, molecular genetic approaches, in vitro biochemical assays, and human bio-samples to examine mitochondrial and cell homeostasis in the lung. See below for more information about our projects:
Project 1: Mitochondrial Repair. The role of ANTs in Epithelial repair, regeneration and cellular senescence – Implications in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)
Idiopathic Pulmonary Fibrosis is a deadly chronic lung disease characterized by epithelial injury and progressive fibrosis. Mitochondrial dysfunction, oxidative stress and cellular senescence, a state of cell growth arrest, have been implicated in disease pathogenesis. I became interested in the role of adenine nucleotide translocases (ANT, canonical mitochondrial ADP/ATP transporters that are critical for mitochondrial respiration) in mitochondrial dysfunction and cell fate. We recently published that ANT1 and ANT2 gene expression are reduced in IPF lung tissue, specifically in alveolar type 2 epithelial cells (AEC2s) which are the regenerative cell type of the alveoli. Furthermore, loss of ANT1 in a bleomycin mouse model of pulmonary fibrosis resulted in exaggerated fibrosis with increased markers of senescence. This exciting work explores a new mechanism for inducing mitochondrial dysfunction and cellular senescence in lung disease. We have preliminary data suggesting that loss of ANT2 in AEC2 cells also results in exaggerated pulmonary fibrosis through increased oxidative stress, reduced AEC2 cell repair in 3D alveolar organoid models and increased cellular senescence. Ongoing studies are further exploring the role of ANTs in chronic obstructive lung disease (COPD) and accelerated lung aging.
Project 2: Macrophage Biology. The role of ANT in the lung macrophages in COPD
Chronic obstructive pulmonary disease (COPD) is characterized by macrophage-driven tissue destruction and chronic inflammation. Mitochondrial metabolism and homeostasis are primary determinants of macrophage function and phenotype. Cigarette smoke (CS) results in mitochondrial dysfunction in numerous cell types. While macrophage phenotypes in advanced human COPD have been explored, the initiating aberrant transcriptional changes that occur in lung macrophages leading to COPD remain unknown. Adenine nucleotide translocase 1 (Ant1) is an ATP transporter critical in mitochondrial metabolism and implicated in macrophage inflammatory function. We utilize ant1-null mice to study the role of macrophage metabolism in COPD pathogenesis. Our preliminary data shows that ant1-null mice are protected against airspace destruction and chronic inflammation after CS exposure. We hypothesize that loss of Ant1 in macrophages results in metabolic dysfunction and immuno-quiescence thus altering early destructive inflammatory pathways in COPD pathogenesis.
Project 3: Airway Epithelial Biology
To discover new biological pathways in lung disease, we leveraged the tractable model organism, Dictyostelium, to identify genes protective against cigarette smoke (CS), a risk factor for COPD, with translation to mammalian systems. We identified that mitochondrial Adenine Nucleotide Translocases (ATP/ADP transporters) provide protection to human airway epithelium from CS-induced injury by increasing airway surface hydration, preserving ciliary beating, enhancing mitochondrial metabolism and maintenance of cell viability. We are interested in identifying therapeutic approaches to modulate ANT2 in the airway epithelium to promote mitochondrial metabolism and airway hydration in obstructive lung diseases.
We found that ANTs moonlight at the plasma membrane in ciliated airway epithelial cells. The airway epithelia have hundreds of motile cilia per cell that synchronously beat to move the mucus layer and particulates out of the airway. The mucus layer remains hydrated due to extracellular ATP and sodium and chloride ion transport. In COPD, there are defects that develop due to CS in epithelial cell survival, mucus hydration and ciliary beating. We demonstrated that ANT2 expression in the human airway epithelium is critical for cell fate, ATP and metabolic state, enhanced airway hydration and ciliary beating. This work described for the first time a unique role for ANTs in lung disease and the therapeutic potential of ANT modulation in protecting from metabolic and epithelial defects, thereby optimizing epithelial cell function.
Paper highlighted in Scientific American:
Project 4: Mitochondrial and Actin Biology. Gelsolin in COPD
The actin cytoskeleton is a dynamic structure that is regulated by actin-binding proteins such as gelsolin. Gelsolin (GSN) acts by severing and capping actin filaments with additional evidence for anti-inflammatory roles. We have found that gelsolin is dysregulated in COPD. Our studies focus on how GSN may promote or protect against disease pathogenesis.