PROJECT SUMMARY/ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease
with suboptimal therapeutics. Fibroblast proliferation, migration, and fibroblast-to-myofibroblast differentiation
(FMD) have been proposed as the major impetus for fibrosis progression. However, recent studies have begun
to reveal great heterogeneity of fibroblasts and myofibroblasts in fibrotic lungs, which appear to contain both
pro-fibrotic/pathologic fibroblasts and anti-fibrotic/reparative/regenerative fibroblasts. Thus, there is a critical
need to better characterize fibroblast populations and to develop therapeutics specifically targeting pro-fibrotic
fibroblasts while concomitantly promoting the expansion of anti-fibrotic fibroblasts.
Dr. Saito’s recent data suggest that inhibition of histone deacetylase 8 (HDAC8) represents such a
strategy. He discovered that: 1) HDAC8 knockdown in lung fibroblasts downregulates expression of genes
encoding pro-proliferative/pro-fibrotic proteins while upregulating expression of genes encoding anti-
migratory/anti-fibrotic proteins; and 2) treatment with an HDAC8-selective inhibitor ameliorates bleomycin-
induced pulmonary fibrosis in mice, likely by activating anti-fibrotic signaling pathways.
Based on these data, Dr. Saito hypothesizes that: 1) inhibition of HDAC8 ameliorates fibroblast
proliferation, migration, and FMD by modifying chromatin structure and then activating transcription of anti-
fibrotic genes; and 2) inhibition of HDAC8 reduces pulmonary fibrosis in vivo by expanding anti-fibrotic
fibroblast subpopulations. Dr. Saito will test these hypotheses with three specific aims. In the first aim, he will
define the effects of HDAC8 inhibition on fibroblast phenotype and gene regulation, using functional assays
(i.e., proliferation assay, migration assay) and sequencing technologies (i.e., RNA-seq, ATAC-seq, ChIP-seq).
In the second aim, he will identify cell intrinsic transcriptional effects of the HDAC8-selective inhibitor in a
bleomycin-induced pulmonary fibrosis mouse model using single-cell RNA-seq, and determine the role of
HDAC8 in cells promoting fibrosis resolution in vivo. In the third aim, he will assess whether mesenchymal cell-
specific HDAC8 knockout mice are protected against bleomycin-induced pulmonary fibrosis and explore types
of cells through which HDAC8 mediates pulmonary fibrosis.
This work will be conducted at Tulane University, under the mentorship of Dr. Jay Kolls (the primary
mentor), a recognized expert in genomics and lung biology, and Dr. Joseph Lasky (co-mentor), a recognized
expert in pulmonary fibrosis, along with advisors who have expertise in genomics and epigenetics. With the
guidance of his mentoring committee, Dr. Saito has developed a comprehensive four-year training program to
develop the skills needed to become an independent investigator with expertise in genomics and epigenetics
of pulmonary fibrosis. His commitment to research, strong mentorship, and the dedication of Tulane to training
the next generation of scientists, will allow him to build a successful career as a physician-scientist.