Mentoring in Translational Interstitial Lung Disease Research

About This Grant

Interstitial lung disease (ILD) comprises a heterogenous group of parenchymal conditions that commonly result in progressive and irreversible pulmonary fibrosis. Once progressive, survival is poor and treatment options limited. Despite these longstanding observations, diagnostic delays remain common. To improve ILD outcomes, innovative approaches to improve early ILD detection and identify new therapeutic targets are urgently needed. As an R01-funded physician scientist engaged in translational ILD research, my long-term goal is to develop clinically actionable, protein-based biomarkers for patients with fibrotic ILD. My lab has already demonstrated the promise of proteomics-based investigation to inform ILD prognostication and has the expertise and resources necessary to leverage proteomics to efficiently address these existing knowledge gaps. The objective of this K24 application is to augment my mentoring capabilities, expand my trainee pipeline and expand upon exciting preliminary data suggesting that a proteomics-based approach can potentially discriminate ILD from other conditions that cause chronic respiratory symptoms and identify proteins that play a potentially causal role in fibrogenesis. Through this award, I will 1) Derive and validate a proteomic biomarker to predict ILD in those with chronic respiratory symptoms and 2) Identify circulating proteins that play a potentially causal role in ILD progression. In Aim 1 I will utilize a medium-throughput, semi-quantitative proteomic array to measure 192 disease relevant proteins in a 500 patient (200 ILD, 300 non-ILD) discovery cohort presenting with chronic respiratory symptoms who underwent contemporaneous chest imaging performed as part of their clinical evaluation. Using machine learning, I will derive a composite protein classifier that discriminates ILD with high sensitivity. I will then apply this classifier to the prospectively recruited validation cohort to determine test performance characteristics. In Aim 2, I will perform causal mediation analysis to discriminate proteins potentially causal of ILD progression from those that represent an epiphenomenon. I will estimate the total, direct and indirect effect of known prognostic biomarkers of ILD survival (exposure) on transplant-free survival (outcome) through declining lung function (mediator). Proteins with survival association that is completely mediated by intermediary progression are most likely to play a causal role in ILD outcomes. Results will be tested in an independent ILD validation cohort. Through this award I will optimize my mentoring skills, expand my training pipeline, and pursue a new line of research that directly benefits these trainees. This K24 award will position me to effectively train a new generation of translational researchers, helping to ensure a sustainable workforce of ILD physician-scientists.