Our long-term goal is to understand the molecular mechanisms of cell-cell interactions during mammalian development and in postnatal physiology. We focus on major signaling pathways, in particular, the Hedgehog (Hh) pathway. The Hh pathway plays a key role in many aspects of embryonic development and dysregulation of Hh signaling is associated with human congenital anomalies and cancers. We have also chosen the mouse lung as a model system to understand organogenesis and adult physiology/pathology. A combination of mouse genetics (transgenic and knockout mice), cell biology, biochemistry and genomic analysis is utilized to address three major issues:
(1) The molecular characterization of the Hedgehog signaling pathway.
We currently investigate how the Hh ligand is produced, lipidated, and transported to generate a morphogen gradient. These studies serve as a paradigm for understanding lipid biology and vesicular trafficking in morphogen gradient formation. We also study the molecular mechanisms by which the Hh signal is transduced in mammals. These studies uncover the involvement of cellular organelles, including the nucleus and the primary/motile cilia in receiving and interpreting the Hh signal, and provide insight into the evolution of developmental pathways.
(2) The role of Hedgehog signaling in various aspects of postnatal physiology and homeostasis such as stem cell maintenance and cancer formation.
The postnatal roles of major signaling pathways remain poorly defined. To address this issue, we have knocked-in an inducible Cre into several genomic loci in mice. These mouse lines, when used in conjunction with mouse strains carrying floxed alleles of major signaling pathway components will allow their inactivation in a temporally and spatially controlled fashion. Taken together, these approaches will enable us to investigate the molecular mechanisms that underlie maintenance of stem cell populations, response to injury/repair, and tumorigenesis.
(3) Lung as a model system to study cell type specification, injury/repair and tumorigenesis.
We have chosen mouse as a model system to answer fundamental questions in lung cell type specification, the molecular process of lung injury/repair and the pathogenesis of lung cancer development. We have combined mouse genetics, cell biology and genomic analysis to tackle these important issues.