Multi-Omics Approaches for the Diagnosis and Risk Stratification of Pulmonary Fibrosis-Associated Pulmonary Hypertension - Project Summary This is an application for a K23 award for Adam J Brownstein, MD, MS, a Pulmonary and Critical Care physician at the University of California, Los Angeles. The goal of this proposal is for Dr. Brownstein to establish himself as independent investigator in patient-oriented research in the field of pulmonary hypertension, with a focus on pulmonary fibrosis-associated pulmonary hypertension (PF-PH). This K23 award will provide Dr. Brownstein with the support to (1) develop proficiency with prospective clinical study design for future multi-institutional studies and clinical trials, (2) develop expertise in the application of multi-omics approaches to PH detection, risk-stratification, and evaluation for lung transplantation in PF-PH, (3) determine the feasibility and utility of developing peripheral blood biomarkers that reflect pulmonary vascular disease severity in PF, (4) become an expert in large data analysis integrating clinical data with omics analyses and advanced statistical modeling, including machine learning approaches, and (5) become an independent translational researcher. Dr. Brownstein is supported by an excellent multidisciplinary mentoring team. Dr. Xia Yang and Dr. Airie Kim, the two primary mentors of this K award, will provide complementary guidance regarding applying multi-omics approaches and translational research design. Dr. Brownstein will also work closely with Dr. Rajan Saggar, a leader in the PH field with expertise in clinical trials and observational cohort studies and Dr. David Elashoff, the leader for the Biostatistics, Epidemiology and Research Design program for the UCLA CTSI. PF is often complicated by the development of PH, leading to significantly reduced survival and increased morbidity. Our preliminary data, which leveraged transcriptomic analysis of explanted lung tissue from patients with PF, has identified a module of genes (referred to as the “tan” module) as potentially pathogenic in PF-PH. However, a better understanding of the cell-specific pathways altered in PF-PH is required to predict those at risk of progressing to clinically significant PF-PH and identify novel therapeutics and biomarkers of disease. This proposal will investigate the PF-PH lung and blood transcriptome by using lung and blood samples collected as part of the UCLA PF and PH biorepository, which includes prospectively collected biospecimens, hemodynamics, echocardiography and other clinical markers of PH. We will also use the PF Foundation Registry to identify a blood transcriptomic signature of PF-PH using machine learning approaches. The specific aims are: 1) Define cell-specific transcriptional changes in lung tissue of PF-PH patients compared to PF-NoPH and PAH, and correlate these findings with clinical markers of disease severity and 2) Evaluate the blood transcriptomic signature of PF-PH patients in order to identify and develop blood biomarkers and predictors of disease. The proposed studies will enable Dr. Brownstein to develop into an independent investigator focusing on PH translational research.
