Multi-omic profiling of IPF endotypes

PROJECT SUMMARY/ABSTRACT This K08 Mentored Career Development Award will provide Dr. Da (David) Zhang with structured mentorship and training towards a goal of developing an independent translational research program to study the genetics of idiopathic pulmonary fibrosis (IPF). IPF is a lethal condition that affects 1 in 200 individuals over the age of 65 with limited treatment options and unresolved genetic influences. Building upon highly original research publications, including the seminal discovery of KIF15 as a novel IPF candidate gene, Dr. Zhang proposes an innovative framework for genetic discovery within endotypes of IPF. He conceptualizes three distinct endotypes of IPF comprising individuals with 1) rare telomere-gene variants, 2) unexplained short telomere lengths, and 3) normal telomere lengths. IPF patients with rare telomere-gene variants or short telomere lengths are known to have worse mortality outcomes; thus this endotype definition is not only biologically grounded but also clinically relevant. This K08 proposal seeks to test the hypothesis that distinct profiles of common variants determine membership in three IPF endotypes and drive characteristic cell type- specific gene expression. Leveraging existing whole genome sequencing (WGS) databases comprising >2100 IPF cases and >12000 controls as well as biobanked lung tissue, this study proposes two independent aims to test this hypothesis. Aim 1 will focus on targeted and genome-wide association studies (GWAS) of IPF stratified by endotype to identify endotype-specific genetic risk factors. Aim 2 centers around single-nucleus transcriptomic and epigenetic analysis of lung explant tissue of patients who have undergone genome sequencing. For this aim, existing cryopreserved lung tissue with known donor genetics as well as prospectively collected lung explants will be used. To complete his research objectives, Dr. Zhang has assembled a multidisciplinary mentoring team and crafted a robust training plan that includes participation in an NIGMS R25-funded Innovative Program to Enhance Research Training (IPERT) already underway. Dr. Zhang will complete training modules in 1) pulmonary genetics, 2) statistical genetics and functional genomics, 3) multi-omics methods, and 4) career development and research dissemination. This K08 proposal will provide Dr. Zhang with the necessary skillset to launch an independent research career. The data generated from this proposal will enable identification of high-priority disease pathways in IPF for future validation in R01 studies.