The overall goal of this project is to combine genetic and genomic findings in patients with idiopathic interstitial pneumonia (IIP) to develop and validate phenotypically anchored molecular signatures that serve to refine the diagnostic criteria for this group of complex diseases. IIP has traditionally been defined by objective clinical characteristics (history, physiology, radiography, and pathology). This approach splits out diseases that appear to be homogeneous including acute interstitial pneumonia (AIP), lymphocytic pneumonia (LIP), and cryptogenic organizing pneumonia (COP) but idiopathic pulmonary fibrosis (IPF), non specific interstitial pneumonia (NSIP), and a group of IIPs that do not fit a specific category remain heterogeneous in terms of overlapping patterns that often defies diagnostic labeling. Substantial evidence supports the concept that these latter categories of IIP, as currently defined, still comprise a heterogeneous phenotype in terms of pattern of presentation, outcome, and response to therapy. It is also possible that even those entities that appear to be homogeneous may in fact comprise mixed groups. For example, what appears clinically to be AIP may, in fact, represent an acute exacerbation of IPF that has hitherto experienced a very indolent and therefore clinically unrecognized course that has developed a rapid explosive phase. While the biological features of IIP are emerging, these molecular attributes (or signatures) that are prototypical of IIP have not yet been integrated with the traditional clinical diagnostic characteristics for these fibrosing interstitial pneumonias. In IIP, gene expression studies from our lab and others have demonstrated unique molecular signatures for some (IPF and familial forms of IIP) but not all (NSIP) forms of this disease. Given the overlapping classification of IIP subtypes and the likelihood that multiple genes play a role in the development of this group of diseases, this is not at all surprising. For instance, about 10% of patients with IIP develop disease due to mutations in either surfactant protein C or telomerase genes, presumably resulting in two distinct molecular signatures. We have recently performed a linkage study in 82 families with = 2 members with probable/definite IIP and have identified regions on chromosomes 10, 11, and 12 that likely contain genes contributing to familial forms of IIP, again presumably resulting in distinct molecular signatures. The compelling challenge is to combine genetic and genomic approaches in patients with IIP to define molecular phenotypes of IIP that can be used to distinguish the clinical aspects of this group of complex diseases. To address this challenge, we hypothesize that the IIP transcriptome is influenced by genetic variants and that, in combination with clinical characteristics, these molecular signatures can be used to refine the diagnostic criteria for this group of complex diseases. To test this hypothesis, we will combine the results of genome-wide RNA expression with regions/genes of interest from genetic studies to develop and validate phenotypically anchored molecular signatures for IIP and its subtypes. (End of Abstract)

R01HL095393

2008-09-24

2013-07-31