Lung Myofibroblast De-Differentiation and Fibrosis Resolution Depend on cAMP-mediated Inhibition of HuR.

Project Summary/Abstract: This proposal describes a five-year research and career development plan intended to support the applicant’s progression to an independent physician-scientist investigating mechanisms of lung myofibroblast (MF) de- differentiation/clearance and pulmonary fibrosis resolution. Research Plan: Idiopathic pulmonary fibrosis (IPF) is the deadliest fibrotic lung disease, affecting millions of individuals worldwide, with limited treatment options that fail to reverse established fibrosis. MFs are the ultimate effector cells of IPF whose persistence following wound repair – a consequence of their apoptosis resistance – leads to progressive lung scarring and stiffness, distorting tissue architecture and impairing gas exchange. Clearance of lung MFs – through their phenotypic de-differentiation and restoration of apoptosis sensitivity – has the potential to resolve fibrosis. The applicant has discovered that lung MF de-differentiation can proceed via distinct transitional phenotypes and that post-transcriptional regulation of mRNAs is crucial to this process. In this proposal, he will investigate the role of the endogenous anti-fibrotic brake cyclic adenosine monophosphate (cAMP) and its regulation of the master post-transcriptional regulator human antigen R (HuR) in MF de-differentiation and fibrosis resolution. Applicant and Training Plan: The applicant holds an MD degree and has completed clinical training in Internal Medicine, Pulmonary, and Critical Care Medicine. During his fellowship and prior research endeavors, he has gained experience with in vitro systems and basic lab techniques in fibroblast biology. As part of his career development, the applicant will participate in mentored research designed to develop new knowledge and proficiency in RNA biology, CRISPR/Cas9 techniques, immunofluorescence microscopy, bioinformatics, and use of novel transgenic mice for in vivo modeling and investigation of pulmonary fibrosis. Acquiring these new skills and experiences will greatly facilitate his development into an independent investigator studying the mechanisms by which MFs can be de-differentiated and cleared, enabling strategies to promote fibrosis resolution. Training in these areas will be acquired under the guidance of his experienced mentoring team, and through participation in seminars, lab meetings, coursework, workshops, and national meetings. He will also receive training in grant writing and responsible conduct of research. The outstanding institutional research environment provides the applicant abundant opportunities for interaction with investigators in RNA and molecular biology, pulmonary and extra-pulmonary fibrosis, as well as with basic and translational scientists. Available facilities for advanced imaging, RNA sequencing, and transgenic animal modeling will be utilized. This application will thus enable a well-trained and committed junior investigator to develop an independent career in the investigation of cellular and molecular mechanisms that can be translated into the resolution of established pulmonary fibrosis – the holy grail of research in this field and an enormous unmet clinical need.