PROJECT SUMMARY/ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic disease characterized with excessively deposited
extracellular matrix (ECM) proteins. Persistent myofibroblast activation is considered as one of driving forces
that lead to excessive ECM protein production and fibrosis in IPF. The molecular mechanisms that perpetuate
persistent myofibroblast activation and pro-fibrotic responses in IPF have not been fully understood. KH-Type
Splicing Regulatory Protein (KSRP) is a mRNA destabilizing protein involved in post-transcriptional regulation of
gene expression. Preliminary data demonstrate that KSRP expression is significantly decreased in IPF lung
fibroblasts and tissues when compared to that in normal human lung fibroblasts and tissues. However, the role
of KSRP in lung fibrosis, and the functional consequences of pathologic KSRP downregulation in pro-fibrotic
responses in IPF, are completely unknown. This proposal aims to reveal the novel restrictive role of KSRP in
lung fibrosis and the molecular mechanisms involved. Preliminary data demonstrate that KSRP deficient mice
have increased lung fibrosis when compared to wild-type mice in response to Bleomycin, and that KSRP
deficiency promotes, while gain of KSRP inhibits, myofibroblast differentiation and ECM protein production.
These data indicate that KSRP functions as a restricting factor of fibrotic reactions, and impaired KSRP function
promotes fibrotic reactions and lung fibrosis. Furthermore, KSRP negatively regulates Migfilin mRNA stability
and expression and KSRP deficiency results in increased Migfilin expression. Our preliminary data demonstrate
that Migfilin functions as a “pro-fibrotic switch”, promoting pro-fibrotic reactions. Migfilin is required for
myofibroblast differentiation and survival. Based on preliminary data, we hypothesize that KSRP functions as a
restrictive regulator of lung fibrosis, and that impaired KSRP function fosters a “pro-fibrotic niche” fueling
persistent myofibroblast differentiation and pro-fibrotic responses mediated by Migfilin and Migfilin mediated
signaling. To test the hypothesis, three specific AIMs are proposed. Specific AIM 1 will determine the
mechanisms by which KSRP regulates myofibroblast differentiation and survival. Specific AIM 2 will determine
the restrictive role of KSRP in controlling ECM expression and matrix assembly. Specific AIM 3 will examine the
in vivo cell-specific role of KSRP in fibrogenesis and functional consequences. The findings will help to
understand the mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF
and serve my long-term goal to develop effective therapy for IPF.