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.