Diversity Supplement (PA-23-189)
Parent Award: R01HL168050-01
Project Title: The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction
Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)
PI: Corrine Kliment, MD, PhD
Applicant Trainee: Ugonna Mbaekwe, B.S.
Abstract:
COPD is a prevalent disease characterized by chronic inflammation, abnormal epithelial repair
and alveolar destruction (emphysema). Major risk factors for COPD include cigarette smoke
(CS) exposure, air pollution and genetics [1,2], leading to millions of affected individuals
worldwide with few effective treatments. We seek to better understand mechanisms of disease
pathogenesis to develop therapies that will halt or reverse COPD development. The objective of
this research project is to determine how adenine nucleotide translocase 2 (ANT2), a prominent
mitochondrial ATP transporter, alters mitochondrial function to influence lung epithelial cell repair
and senescence in smoking-induced lung injury and COPD. The research performed under this
diversity supplement is an integral part of the approved, ongoing research under the parent
R01. The parent R01 has 3 primary aims: 1) To test the hypothesis that loss of ANT2 in AEC2
cells drives senescence by increasing ROS and the DNA damage response (DDR). 2) To test
the hypothesis that loss of ANT2 shifts AEC2 metabolism and decreases repair capacity to
promote COPD; and 3) To test the hypothesis that therapeutic restoration of ANT2 or removal of
senescent cells can protect against emphysema. This diversity supplement will specifically
focus on the mechanism of senescence and ferroptosis, a form of cell death, in lung repair. The
connection between ferroptosis and senescence in lung disease remains unknown. Research
under this supplement will evaluate novel links between the senescence and ferroptosis
pathways in the context of the parent R01 studies. This is an exciting and logical extension of
the studies outlined in the R01.
