Research Interests

Project 1: 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 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: https://www.scientificamerican.com/article/treating-a-deadly-lung-disease-with-a-little-help-from-amoebas/

Kliment CR, Nguyen JM, Kaltreider MJ, Lu YW, Claypool SM, Radder JE, Sciurba FC, Zhang Y, Gregory AD, Iglesias PA, Sidhaye VK. Robinson, DN. (2021) Adenine Nucleotide Translocase regulates airway epithelial metabolism, surface hydration, and ciliary function. J Cell Science. Feb 1, 2021.