The overall focus of the Ornitz laboratory is on in vivo functions of Fibroblast Growth Factors (FGFs), their interactions with other signaling pathways, and their role in tissue regeneration, response to injury, and cancer. We use in vivo mouse models to study mechanisms of organogenesis and apply our knowledge of developmental processes to understand mechanisms regulating tissue homeostasis, and reactivation of developmental programs in oncogenesis and in tissue regeneration in response to injury.
Cardiovascular system: We are investigating the function of FGF receptor signaling in specific cardiovascular lineages. We have shown that endothelial FGF receptor signaling is essential for wound healing, and the hearts response to ischemia-reperfusion injury. FGF receptors are being targeted in cardiomyocytes and stromal cells of the heart and other tissues to address their role in tissue homeostasis, and ischemia-reperfusion injury.
Respiratory system: We are investigating how FGF, Wnt, and BMP signaling pathways interact to regulate growth of the lung and the complex process of branching morphogenesis. We are investigating mechanisms by which micro RNAs and other epigenetic factors regulate Fgf9 expression during development and in the pathogenesis of Pleuropulmonary Blastoma, a familial pediatric lung cancer syndrome that is initiated by mutations in DICER1. We are investigating mechanisms by which FGFs are protective in lung epithelial repair and pathogenic in pulmonary fibrosis, and we are investigating mechanisms by which FGF signaling activates adult lung progenitor cells in models of adenocarcinoma and response to injury.
Skeletal system: We are investigating how FGF signaling regulates osteoblast function and bone density during development and aging. We have shown that FGF signaling in the osteoprogenitor cell indirectly regulates growth plate chondrocyte proliferation and differentiation and directly regulates the metabolic activity of osteoblasts. We have also identified an autocrine FGF signal that regulates articular chondrocyte differentiation. Through these mechanisms, FGF signaling regulates longitudinal bone growth, bone mass, and homeostasis of articular cartilage.
Inner ear and olfactory development and regeneration: We have identified FGF20 as an essential signal that regulates the development of sensory receptors in the inner ear. Mice lacking FGF20 are viable, healthy and congenitally deaf. FGF20 expression also marks a progenitor cell lineage in the olfactory epithelium and functions to regulate the growth of the underlying nasal turbinates. Our aims are to identify the molecular mechanisms that regulate the expression of Fgf20 during embryonic development of the cochlea and olfactory epithelium; to determine how FGF20 regulates sensory progenitor cell growth and the differentiation of cochlear outer hair and supporting cells in the organ of Corti; and to identify the specific genes and pathways that act downstream of FGF20 during cochlear and olfactory development using Next Gen mRNA sequencing. We are testing the hypothesis that FGF signaling can enhance sensory cell regeneration following ototoxic damage.