This is an application for F32 fellowship support for two years. During the fellowship period, the applicant will work on elucidating the role of Hedgehog (Hh) signaling in postnatal lung development. Hh signaling is mediated by three similar proteins (Sonic, Indian and Desert Hh) acting on the cell receptor Patched, and typically affects function of mesenchymal cells. Hedgehog signaling has been known for some time to be critical during embryonic development, but only recently has it come to be appreciated that Hh signaling affects disease processes such as cancer and fibrosis. Hedgehog signaling plays a major in branching morphogenesis in embryonic lung development but it is currently unknown what role this pathway plays during the final developmental steps of the lung. This final, postnatal phase of lung development involves creation of secondary septa, and maturation of these septal walls in a poorly understood process involving loss of interstitial cells. It is also postulated that developmental pathways such as Hh are reactivated in pulmonary fibrosis. The research plan is designed to test the hypothesis that proper timing of Hh signaling down-regulation is critical for the proper maturation of septal walls. The hypothesis states that Hh signaling in early postnatal lung development supports vigorous expansion of mesenchymal cells, whereas withdrawal of signaling at the end of the alveolarization phase contributes to a relative loss of mesenchymal cells due to some combination of reduced proliferation and increased apoptosis.
The Aims to test this consist of, first, detailed analysis of the precise timig of Hh signaling during this period, measured using reporter mice that read-out Hh signaling, measurement by qRT-PCR of downstream transcriptional targets of Hh signaling such as Gli1, and direct measurement of Shh protein levels. In addition, in the second Aim, the effects of augmenting or inhibiting Hh signaling during the two phases will be determined and compared with predictions based on the hypothesis. To pursue this work and training, the applicant will work in the basic science lab of Dr. Dan Rifkin, acting chair of Cell Biology at NYU, who has a strong mentoring record and a wide range of research interests (cancer, fibrosis, and development of lung, heart and bone) that have extracellular matrix biology as a common thread. He will also pursue graduate level course work in Cell Biology, developmental systems, and stem cell biology, along with focused work related to grant writing, presentation skills and the ethical conduct of research. This research experience and related training are designed to augment his prior extensive research experience in pulmonary fibrosis and leave him poised to investigate questions of lung development, lung fibrosis and injury, and the involvement of developmental signaling pathways in adult lung processes and disease.
Lung injury and disease may involve the inappropriate re-activation of signaling pathways used during development. This research project and F32 training program are designed to lead to better understanding of the Hedgehog signaling pathway in postnatal development of the lung and provide the foundation for better understanding its possible role in diseases such as bronchopulmonary dysplasia, COPD and fibrosis.
|Kugler, Matthias C; Joyner, Alexandra L; Loomis, Cynthia A et al. (2015) Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol 52:1-13|