This story has been updated from a previous version to include additional comments from the researchers.
The National Institutes of Health have awarded a four-year, $2.9 million grant to the Boston University School of Medicine to study the genetic underpinnings of chronic obstructive pulmonary disease, BUSM said last week.
BUSM received the NIH funding to use genomic technologies to better understand lung disease, in this case COPD, a disease associated with smoking that is characterized by airflow constriction and that often leads to lung cancer.
According to the university, the study, which will use arrays made by Affymetrix and Invitrogen, aims to develop an understanding of the processes that contribute to COPD pathogenesis that will ultimately yield tools to stratify and treat COPD patients based on the molecular processes that are responsible for the disease.
Principal Investigator Avrum Spira, an associate professor of medicine and pathology at BUSM, said this week that he and fellow PI Marc Lenburg plan to use Affymetrix exon arrays and Invitrogen microRNA arrays to survey up to 800 patient samples for biomarkers linked to COPD with the ultimate goal of bringing the discoveries into clinical use.
“Our hypothesis is that some of the mRNA changes we are seeing in lung cancer are related to changes in microRNAs, and that we can narrow in on a small number of miRNAs that essentially regulate the large number of mRNAs that change when you smoke,” Spira told BioArray News this week.
According to the National Heart, Blood, and Lung Institute, COPD is the fourth-leading cause of death in the United States. It is estimated that the disease is diagnosed in 12 million people in the US, while another 12 million cases go undiagnosed.
Spira, who said he spends 30 percent of his time in the clinic and the rest in the lab, said that approaches to diagnosing and managing COPD are lacking, and that COPD patients typically exhibit clinical heterogeneity.
“I am trying to drive this project from a clinical perspective,” he said. “My hope one day is that we will use these platforms in the clinic.”
Spira said in a statement last week that his lab has previously shown that “cigarette smoke affects the entire respiratory tract, and that we can detect signs of disease-specific processes occurring deep in the lung by examining, using microarray technology, the pattern of genes that are turned on and off in the relatively accessible cells at the top of the airway.”
In the statement, Lenburg said the team will use this approach to identify the molecular processes that give rise to COPD in individual patients. “Our hope is that this will give us some important clues about what underlies the symptomatic differences seen between patients, and that ultimately we will be able to tailor which therapies a patient receives for their COPD based on these differences," he said.
mRNA and miRNA
So far in its research, Spira’s lab has used Affymetrix whole-genome gene-expression arrays to study gene-expression profiles in airway epithelial cells, which are harvested during bronchoscopy. “We are able to brush, collect, and get RNA out of these cells that we run on microarrays,” Spira said.
“We know there is an epidemiological link between these diseases. If you get COPD, you are likely to get lung cancer.”
Over the past year, though, the lab has begun integrating Invitrogen’s NCode microRNA arrays into its studies. “We have been measuring miRNA expression using the same cells we get from the airway,” said Spira. “We are basically able to look at the relationship between the miRNA and mRNA in the same tissue and see what changes with smoking and what changes with cancer.”
To do that, BUSM will look at around 340 COPD patient samples collected by the University of British Columbia in Canada. “They have collected samples from hundreds of smokers who are enrolled in a screening trial for lung cancer in Canada,” said Spira
According to Spira, those smokers who do not have lung cancer often have COPD, as measured by pulmonary function testing. Spira and Lenburg plan to look at patients with and without COPD; look at their airway epithelial cells; and look at differences in gene expression due to smoking.
“We know there is an epidemiological link between these diseases,” Spira said. “If you get COPD, you are likely to get lung cancer. So the goal of this study is to look at this cohort and see if we can correlate differential gene-expression response with presence or absence of COPD,” he added.
A bonus of the study will be that UBC’s cohort has already been followed for more than 10 years. “We will also be able to follow these individuals over that time frame and see who did well and who did not, and develop a predictor of outcome with COPD,” said Spira.
In terms of data analysis, the team will be looking at data from the two different array platforms, and has decided to build its own bioinformatics infrastructure. “We are going to look for predictions in our data and correlate that with known examples of miRNA regulating mRNA, to develop a sense of which miRNA may be regulating gene expression in the airway,” Spira said. “We then go in vitro with cell lines and prove that the miRNA regulated the mRNA expression by modulating the level of the microRNA and studying the level of gene expression downstream.”
Lenburg told BioArray News this week that “filtering all the potential regulatory miRNA-mRNA relationships to those that seem most likely and worth testing experimentally is computationally daunting.” Lenburg said that he and Spira will work with James Collins’ group at the BU College of Engineering on applying methods developed for identifying regulatory networks from gene-expression data, to the problem of identifying miRNA-mRNA regulatory networks.