The primary objective of this proposal is to characterize the genetic and genomic profiles of those who develop, and progress from, early stages of pulmonary fibrosis (PF). Idiopathic pulmonary fibrosis (IPF), the most common and severe form of PF, has a mortality rate comparable to that of many end-stage malignancies. Despite advances in medical therapy for IPF, it is becoming increasing recognized that further attempts to improve outcomes for patients with IPF will need to additionally focus on preventing very early, but detectable, stages of PF from progressing to the end-stages of PF that help to define IPF. Recent evidence has demonstrated that research participants with particular patterns chest CT abnormalities (termed interstitial lung abnormalities [ILA]) can have a syndrome similar to that observed in IPF patients. Insights from this work include the fact that although ILA are more prevalent (7-9% in adults > age 50) than IPF is reported to be (0.002-0.04% of the population), research participants with ILA can have genetic predictors noted in IPF patients, restrictive physiologic and exercise impairments, radiologic progression, accelerated lung function decline, and an increased risk for death. Based on these findings, we hypothesize that ILA, in some cases, represent and early/mild stage of IPF which will result in a substantial overlap in the genetic and genomic predictors between these two conditions. Furthermore, we hypothesize that comprehensive genetic and genomic profiles of early/mild stages of PF, will not only improve our understanding of early disease pathogenesis, but can also be translated into clinical tests that will help to determine those who are at the greatest risk to develop, and progress, from PF. To address these hypotheses we propose the following specific aims:
Aim 1) Can genetic profiles be identified in those who develop, and progress from, early stages of PF? Aim 2) Can lung and peripheral blood genomic profiles be identified in those who develop, and progress from, early stages of PF? And Aim 3) Can the integration of clinical, as well as genetic and genomic data improve our understanding of early disease pathogenesis, and enable early disease detection for, PF? The results of these studies will improve our understanding of early disease pathogenesis in PF, as well as setting the stage for trials aimed at the early institution novel and existing medical therapies in those at risk for IPF.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is a disorder characterized by lung scarring and has a prognosis worse than that of most cancers. Identifying IPF at very early, but detectable, stages could lead to earlier treatment and improved outcomes for those at risk for this disease. Improving our understanding of early disease pathogenesis could lead to newer, more targeted, medical therapies. This proposal aims to improve our understanding of both early disease pathogenesis, and detection, by providing a comprehensive characterization of the genetic and genomic characterization predictors of those at risk to develop pulmonary fibrosis in general, and IPF in particular.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Vuga, Louis Justine
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Brigham and Women's Hospital
United States
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