Mechanistic Studies of Hedgehog Signaling in the Lung

New York University School Of Medicine, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Adult lung diseases with parenchymal scarring, such as idiopathic pulmonary fibrosis (IPF), cause significant morbidity and mortality. Current IPF treatment does not prolong survival. In IPF, lung fibroblasts accumulate in scars, producing extracellular matrix that ultimately destroys normal lung structure. Developmental signaling pathways, such as Sonic Hedgehog (SHH) signaling, have been implicated in IPF, consistent with their roles in regulating fibroblasts during lung growth. We revealed SHH signaling in lung fibroblasts during postnatal lung development and in an experimental IPF model. The long-term goals of this project are to better understand the molecular signatures of pulmonary fibrosis by studying their characteristics in pathophysiologically relevant mouse models to elucidate novel mechanisms and improve treatment options. The proposed study will use our postnatal model to define the physiologic effect of SHH on lung fibroblasts, in order to inform the likely pathological effects of SHH signaling in lung fibrosis. We hypothesize that SHH signaling regulates lung fibroblast function during alveolar septal wall maturation in postnatal lung and during the persistent state of pulmonary fibrosis. In Aim 1 we will correlate spatiotemporal changes in SHH signaling with cellular and molecular events in lung fibroblasts during postnatal lung development. We will employ genetic reporters to assess proliferation, apoptosis, senescence, and electron microscopy to assess septal wall maturation. We will determine the effects of pharmacological and genetic augmentation and reduction of SHH signaling during specific phases of postnatal lung development (alveolarization and maturation) on lung fibroblasts and lung structure. Transcriptome profiles of FACS-sorted HH-responding fibroblasts isolated at critical time points of the alveolarization phase will be examined by RNAseq to reveal candidate genes that could be used as targets to decrease fibroblasts in adult fibrosis. In Aim 2 we will address whether SHH signaling retards resolution or promotes persistence of fibrosis in a well-characterized experimental model, and elucidate the involvement of important mechanisms by which SHH signaling affects fibroblasts and myofibroblasts. These studies will be performed under the mentorship of Dr. Daniel Rifkin, an expert in matrix biology, and the co-mentorship of Dr. Alexandra Joyner, an expert in organ development, HH signaling and mouse genetics, and Dr. John Munger, expert in lung development and pulmonary fibrosis. The mentors and their laboratories, together with the expertise of NYU core facilities on specific techniques, provide the optimal setting for developing expertise in the techniques and methodologies required for future success in the field of pulmonary fibrosis research after my transition to an independent faculty position.