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UCSF Team Using NHLBI Grant to ID Lung Disease Protein Markers in Premature Infants

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NEW YORK (GenomeWeb) – Under a new National Institutes of Health grant awarded this month, a University of California San Francisco team plans to search samples from two existing cohorts of premature infants to identify proteomic biomarkers associated with poor outcomes from early lung disease and hopefully.

The researchers, led by UCSF's Phillip Ballard, also hope to lay the groundwork for the development of targeted interventions to prevent such outcomes in these newborns. The investigators were funded $198,125 this month by the National Heart, Lung, and Blood Institute for the first year of the two-year project.

Ballard told GenomeWeb this week that infants born prematurely are at risk for a chronic lung complication called bronchopulmonary dysplasia. This early lung dysfunction can eventually lead to later respiratory disorders including asthma, and is also a major cause of morbidity among premature infants, despite current approaches to both prevention and intensive care.

"Currently we don't have any good biomarkers — nothing established at least," Ballard said. "People have looked at specific cytokines, growth factors, mediators in small studies – and found some associations with outcome, but it's never been fully defined and the pathways haven't been fully investigated, at least not to the point where we have any interventions based on a biomarker."

"That's now our goal — to develop a marker in some compartment, for example tracheal aspirate, urine, or plasma, with which we could identify these infants early in their clinical course and hopefully apply interventions targeted at the specific pathway involved," he added.

Ballard and colleagues proposed their study in response to a funding opportunity for investigations of existing longitudinal cohorts to generate new clinical, biological, and genomic data to better define chronic lung diseases.

Under their new NHLBI funding, Ballard and his team plan to combine two recent cohorts of well-phenotyped, very premature infants for which there exist archived samples of tracheal aspirate, urine, and also DNA in order to examine associations between proteins and the cohorts' existing longitudinal measures of pulmonary outcome.

One cohort will be supplied by the Trial Of Late Surfactant (TOLSURF), a multicenter interventional trial conducted across 25 US hospitals that recruited and followed 511 infants through 24 months.

Another 835 study subjects will come from the Prematurity and Respiratory Outcomes Project (PROP), which was originally conducted at 13 centers, and investigated molecular mechanisms that contribute to risk for continuing respiratory disease in infants with initial lung problems.

"Our big advantage is that we have these 1,000-plus infants and they are heavily phenotyped so we know a lot about their clinical course and their other diseases and also a lot of detail about medications with follow up through one year of age. That gives us a lot of power to look at relationships between a biomarker and clinical course," Ballard said.

In their study, he and his colleagues plan to use a mass spectrometry-based global proteomic approach to identify proteins in neonatal lung fluid that are associated with eventual poor respiratory outcomes. The team will then validate the most promising markers using ELISA, Ballard said.

As a second aim, the researchers will also look for urinary proteins associated with first-year respiratory morbidity, according to their grant abstract.

The mass spec work will be conducted in the laboratory of UCSF researcher Al Burlingame. "We have some preliminary data indicating we can resolve about 400 different proteins in tracheal aspirate, and we have some very preliminary data that there are biomarkers that distinguish between infants that do well and those that go on to have chronic lung disease," he said.

"We'll be pursuing that with more samples and following up with ELISA assays to confirm and validate. Hopefully we will identify a small family of proteins that … reliably predict how these infants will do and how they may respond to therapeutic intervention."

According to the researchers, the study will gain statistical power through the use of an extreme phenotype approach, in other words, by strictly defining comparison groups as infants with no lung disease in the first year versus groups that go on to develop disease in each quarter of that same year of life.

According to Ballard, the most likely outcome of the team's global proteomics exploration in these two cohorts will be a small panel of proteins.

"We could get lucky and get one key target protein, but more likely I think a handful may serve as the best panel to look at," he said.

Though not a part of the team's current study, Ballard said the eventual hope is that the results will lead to investigation of existing drugs linked to pathways the group discovers, or potentially development of novel targeted therapies.

"For example one possibility might be the TGF-b pathway, which we know has effects in the lung," he said. "If we can identify markers of TGF-b status or activity – that would give rationale for developing a drug or using existing drugs that would target that pathway."

Even without the identification or development of pathway-specific therapies, having biomarkers that define premature infants' risk of poor respiratory outcomes could also potentially have benefit on its own, Ballard said.

"There would be some benefit if you could identify these infants early and physicians and family would know what the expected outcome is, so you could maybe use existing interventions more rationally or rapidly," he explained.

"Or, a longer-term benefit might be identifying infants early who are at high risk for a bad outcome, and using that population for an intervention trial with a new medicine. That way, the risk-benefit ratio would be better because you wouldn't be treating infants with low risk. But that's all obviously waiting on our results in this initial study," Ballard said.

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