PROJECT SUMMARY / ABSTRACT
Fibrosis is the excessive excretion of extracellular matrix (ECM) proteins, which leads to tissue stiffening and
decreased organ function. Fibroblasts and myofibroblasts are the primary cell types responsible for ECM
deposition. Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic disease of unknown origin. The role of
biochemical signaling through the TGFb signaling pathway is a well-established driver of IPF and other fibrotic
disease. There is also an emerging and evolving role for mechanical signaling in the regulation of ECM deposition
in fibroblasts and the progression of fibrosis. The molecular mechanism by which mechanical inputs are
integrated with biochemical signals to regulate fibrosis remains enigmatic. Work from our lab has implicated the
Linker of Nucleoskeleton and Cytoskeleton (LINC) complex as a new regulator of fibrosis; ablation of the LINC
complex component SUN2 in a Sun2-/- mouse model is protective in the context of hypertrophy-coupled cardiac
fibrosis and injury-induced lung fibrosis. Given the established role of LINC complexes in transmitting mechanical
force from the cell surface to the nucleus, a compelling hypothesis is that LINC complexes contribute to
mechanotransduction during fibrosis progression. The overall objective of this proposal is to define the
molecular mechanisms by which loss of SUN2 leads to protection from fibrosis.
The proposed research will investigate this objective in two specific aims. Aim 1 will define the integration
of biochemical (modulating TGFb and TGFb receptor) and mechanical (modulating cell substrate stiffness) inputs
in the regulation of pro-fibrotic gene expression and attainment of pro-fibrotic phenotypes in primary human and
mouse lung fibroblasts. The contexts and mechanism by which SUN proteins influence integration of pro-fibrotic
signals to regulate gene expression will be interrogated using CRISPR-based gene editing, transcriptome
analysis, and imaging techniques. Aim 2 will define the impact of loss of SUN proteins on both chromatin state
and the established transducers of TGFb signaling, the Smad family of transcription factors, using a combination
of genomic techniques and imaging approaches. This proposal will address fundamental aspects of gene
regulation as it pertains specifically to the progression of lung fibrosis, in line with the mission of the
National Heart, Lung, and Blood Institute.
The trainee will be immersed in a supportive, collaborative and interdisciplinary environment while
completing the proposed project under the rich support and mentorship of the sponsor/co-sponsor, ultimately
positioning her to approach fundamental questions through a translational lens. She will improve her
experimental design skills, obtain training in rigorous analysis of experimental data, and expand her technical
skillset to include methods from genomics to imaging of tissue. The trainee will also have ample access to
opportunities for improving oral presentation, writing, mentorship, scientific outreach skills.