NIH Renews Grant to Research Mechanisms of COPD and IPF
A $12.8 million five-year renewal grant from the National Institutes of Health (NIH) will fund research that seeks to better understand the molecular mechanisms that drive chronic obstructive pulmonary disease (COPD) and other lung diseases.
The research also aims to increase understanding of how cigarette smoking affects the development of these diseases.
The grant — from the NIH’s National Heart, Lung, and Blood Institute (NHLBI) — was awarded to a team of researchers from Weill Cornell Medicine, Brown University, Brigham and Women’s Hospital, and the Harvard T. H. Chan School of Public Health.
In prior work supported by a five-year $11.5 million Program Project Grant (PPG), these researchers identified two molecular pathways that appear to be involved in COPD and another lung disease, idiopathic pulmonary fibrosis (IPF), which is characterized by lung scarring (fibrosis). Now, the team is aiming to investigate further and build on its prior findings.
“Our team of world-renowned experts in COPD and IPF research achieved some noteworthy milestones in the first funding cycle. We are excited to build on our momentum with this grant renewal,” Augustine M.K. Choi, MD, said in a press release. Choi is a pulmonologist at Weill Cornell Medicine and the study’s principal investigator.
Researchers’ prior work had focused specifically on two pathways: the mitochondrial and the chitinase pathway.
The mitochondrial pathway involves the small structures famous for being the “energy factories” of cells, called mitochondria. Specifically, this pathway involves a protein, called PINK1, which regulates how cells get rid of damaged mitochondria.
Prior research showed that lacking PINK1 was protective against emphysema, a severe form of COPD. Yet, at the same time, lacking PINK1 spurred the development of IPF. The mitochondria-associated protein also affected the activity of another signaling protein that is known to control cell death.
“Damaged mitochondria release mitochondrial DNA that can be detected in urine and blood. Our PPG team recently found that urine testing outperformed blood testing for detecting mitochondrial DNA in animal studies, suggesting that it may be a valuable biomarker for determining the severity of COPD and IPF in humans,” Choi said.
The chitinase pathway involved a protein called Chi3l1, which is known to play a role in inflammation and tissue remodeling. In prior studies, scientists found this protein interacts with signaling molecules that are associated with the development of COPD and IPF in mouse models. Prior data also suggested that this pathway might overlap with the mitochondrial pathway.
“Because chitinase-like proteins can also be detected in the urine, we also look forward to investigating their utility as a urinary biomarker of disease severity,” said Jack Elias, MD, dean of medicine and biological sciences at Brown University.
The newly funded project has three main goals. The first two are to further characterize these two disease-linked pathways.
“We are looking forward to working with our colleagues to investigate and enhance our understanding of the interactions of chitinases and chitinase-like proteins and mitochondria and their roles in pulmonary inflammation, remodeling and repair in idiopathic pulmonary fibrosis and COPD,” Elias said.
The third goal of the project is to better understand how smoking cigarettes increases the risk for both COPD and IPF. Using data from the COPDGene study and other datasets, researchers will analyze thousands of patient samples. They will then look at patterns of DNA methylation — a chemical modification added to DNA that affect the way genes are expressed, or “read.” It is thought that cigarette smoking might alter these chemical modifications.
Researchers also will use information from the datasets to conduct investigations related to the mitochondrial and chitinase pathways.
“The focused studies of key biological pathways for the development of COPD and IPF using comprehensive assessments of multiple biological layers in large, well-characterized human populations has the potential to identify the networks of interacting molecular determinants that influence risk for different chronic lung diseases,” said Edwin Silverman, MD, PhD, a professor at Harvard and project investigator.
“Our program has significant potential for revealing new insights into the biological mechanisms driving these devastating diseases,” Choi said.
“We hope our comprehensive approach will identify new biological targets that may lead to the first effective treatments for these diseases and reveal useful biomarkers for stratifying patients by risk in future clinical research,” he added.